Amino-pyrrolopyrimidinone compounds and methods of use thereof

ABSTRACT

The application relates to a compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of BTK, a pharmaceutical composition comprising a compound of Formula (I), and a method of treating or preventing a disease in which BTK plays a role.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/683,913, filed onAug. 23, 2017, which claims priority to, and the benefit of, U.S. Ser.No. 62/378,868, 62/378,871, and 62/378,872, each filed on Aug. 24, 2016,the contents of each of which are incorporated herein by reference intheir entirety.

FIELD OF THE APPLICATION

The present application is directed to inhibitors of Bruton's TyrosineKinase (BTK), including mutant BTK, useful in the treatment of diseasesor disorders associated with BTK kinase, including immune disorders,cancer, cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders, and neurological disorders.Specifically, the application is concerned with compounds andcompositions thereof, which inhibit BTK, methods of treating diseases ordisorders associated with BTK and methods of synthesis of thesecompounds.

BACKGROUND

BTK is a member of the Tec family of tyrosine kinases and plays animportant role in the regulation of early B-cell development and matureB-cell activation and survival (Hunter, Cell, 1987 50, 823-829).Functioning downstream of multiple receptors, such as growth factors,B-cell antigen, chemokine, and innate immune receptors, BTK initiates anumber of cellular processes including cell proliferation, survival,differentiation, motility, angiogenesis, cytokine production, andantigen presentation.

BTK-deficient mouse models have shown the role BTK plays in allergicdisorders and/or autoimmune disease and/or inflammatory disease. Forinstance, BTK deficiency in standard murine preclinical models ofsystemic lupus erythematosus (SLE) has been shown to result in a markedamelioration of disease progression. Furthermore, BTK-deficient mice canbe resistant to developing collagen-induced arthritis and lesssusceptible to Staphylococcus-induced arthritis. Due to BTK's role inB-cell activation, BTK inhibitors can also be useful as inhibitors ofB-cell mediated pathogenic activity (such as autoantibody production).Expression of BTK in osteoclasts, mast cells and monocytes has beenshown to be important for the function of these cells. For example,impaired IgE-mediated mast cell activation and reduced TNF-alphaproduction by activated monocytes has been associated with BTKdeficiency in mice and humans. Thus, BTK inhibition can be useful forthe treatment of allergic disorders and/or autoimmune and/orinflammatory diseases such as: SLE, rheumatoid arthritis, multiplevasculitides, idiopathic thrombocytopenic purpura (ITP), myastheniagravis, allergic rhinitis, and asthma (DiPaolo et al., Nature Chem.Biol. 2011, 7(1):41-50; Liu et al., Jour. Pharmacol. and Exp. Ther.2011, 338(1):154-163).

Moreover, BTK's role in apoptosis demonstrates the utility of inhibitionof BTK activity for the treatment of cancers, B-cell lymphoma, leukemia,and other hematological malignancies. In addition, given the role of BTKin osteoclast function, inhibition of BTK activity can be useful for thetreatment of bone disorders such as osteoporosis.

Inhibition of BTK with small molecule inhibitors therefore has thepotential to be a treatment for immune disorders, cancer, cardiovasculardiseases, viral infections, inflammation, metabolism/endocrine functiondisorders, and neurological disorders. Thus, there remains aconsiderable need for potent small molecule inhibitors of BTK.

SUMMARY

A first aspect of the application relates to a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, wherein R₁, R₂, R₃, A, and q are as described indetail below.

Another aspect of the application relates to a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application relates to a method of treating aBTK-mediated disorder. The method comprises administering to a subjectin need of a treatment for a disease or disorder associated withmodulation of BTK kinase a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,prodrug, stereoisomer, or tautomer thereof.

Another aspect of the application relates to a method of treating aBTK-mediated disorder. The method comprises administering to a subjectin need of a treatment for a disease or disorder associated withmodulation of BTK kinase a therapeutically effective amount of apharmaceutical composition comprising a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof, and a pharmaceutically acceptable diluent, excipientor carrier.

Another aspect of the application relates to a method of treating a cellproliferative disorder. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the application relates to a method of treating a cellproliferative disorder. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application relates to a method of treatingcancer. The method comprises administering to a subject in need thereofa therapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof.

Another aspect of the application relates to a method of treatingcancer. The method comprises administering to a subject in need thereofa therapeutically effective amount of a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, prodrug, stereoisomer, or tautomer thereof, and apharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application relates to a method of modulating(e.g., inhibiting) BTK. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the application relates to a method of modulating(e.g., inhibiting) BTK. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application relates to a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, for use in a method of treating a BTK-mediateddisorder, a cell proliferative disorder, or cancer, or of modulating(e.g., inhibiting) BTK. The compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof, is administered in a therapeutically effective amountto a subject in need thereof.

Another aspect of the application relates to a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,and a pharmaceutically acceptable diluent, excipient or carrier for usein a method of treating a BTK-mediated disorder, a cell proliferativedisorder, or cancer, or of modulating (e.g., inhibiting) BTK. Thecomposition is administered in a therapeutically effective amount to asubject in need thereof.

Another aspect of the application relates to the use of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating a BTK-mediated disorder, a cell proliferative disorder, orcancer, or for modulating (e.g., inhibiting) BTK. The compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof, is administered in a therapeuticallyeffective amount to a subject in need thereof.

Another aspect of the application relates to the use of a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,and a pharmaceutically acceptable diluent, excipient or carrier in themanufacture of a medicament for treating a BTK-mediated disorder, a cellproliferative disorder, or cancer, or for modulating (e.g., inhibiting)BTK. The composition is administered in a therapeutically effectiveamount to a subject in need thereof

The present application further provides methods of treating a diseaseor disorder associated with modulation of BTK kinase including, but notlimited to, immune disorders, cancer, cardiovascular diseases, viralinfections, inflammation, metabolism/endocrine function disorders, andneurological disorders comprising, administering to a subject sufferingfrom at least one of the diseases or disorders a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof.

The present application provides inhibitors of BTK that are therapeuticagents in the treatment of diseases such as immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders, neurological disorders andother disease associated with the modulation of BTK kinase.

The present application further provides compounds and compositions withan improved efficacy and safety profile relative to known BTKinhibitors. The present application also provides agents with novelmechanisms of action toward BTK kinase in the treatment of various typesof diseases including immune disorders, cancer, cardiovascular diseases,viral infections, inflammation, metabolism/endocrine function disorders,and neurological disorders. Ultimately the present application providesthe medical community with a novel pharmacological strategy for thetreatment of diseases and disorders associated with BTK kinase.

DETAILED DESCRIPTION Compounds of the Application

The present application relates to compounds and compositions thereofthat are capable of modulating the activity Bruton's Tyrosine Kinase(BTK). The application features methods of treating, preventing orameliorating a disease or disorder in which BTK plays a role byadministering to a subject in need thereof a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, prodrug, stereoisomer, or tautomer thereof. The methodsof the present application can be used in the treatment of a variety ofBTK-mediated diseases and disorders by inhibiting the activity of BTKkinase. Inhibition of BTK provides treatment, prevention, oramelioration of diseases including, but not limited to, immunedisorders, cancer, cardiovascular diseases, viral infections,inflammation, metabolism/endocrine function disorders and neurologicaldisorders.

In a first aspect of the application, a compound of Formula (I) isdescribed:

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, wherein:

A is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S, wherein the aryl and heteroarylare optionally substituted with one or more R₄;

R₁ is (C₃-C₇) cycloalkyl or 4- to 9-membered heterocyclyl comprising 1to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl andheterocyclyl are optionally substituted with one or more R₅;

R₂ is H or (C₁-C₄) alkyl; or

when q is 0, R₁ and R₂ together with the nitrogen atom to which they areattached form a 5- or 6-membered heterocyclyl ring comprising 0 to 1additional heteroatoms selected from N, O, and S and optionallysubstituted with one or more NR₆R₇;

R₃ is H or N(R₅)₂;

each R₄ is independently (i) (C₁-C₄) alkyl, (ii) (C₁-C₄) alkoxyoptionally substituted with one or more (C₁-C₄) alkoxy, (iii) (C₁-C₄)haloalkyl, (iv) (C₁-C₄) haloalkoxy, (v) halogen, (vi) NR₉S(O)_(p)R₁₀,(vii) O(CH₂)_(n)R₁₁, (viii) NH(CH₂)_(n)R₁₁, (ix) (CH₂)_(n)C(═O)NHR₂₅,(x) (CH₂)_(n)NHC(═O)R₂₅, (xi) (CH₂)_(n)NHC(═O)NHR₂₅, (xii) C(═O)R₂₅, or(xiii) heterocyclyl comprising one or two 4- to 6-membered rings and 1to 3 heteroatoms selected from N, O, and S and optionally substitutedwith one or more substituents selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, C(═O)(C₁-C₄) alkyl, and halogen;

each R₅ is independently (i) (C₁-C₆) alkyl optionally substituted withone or more (C₁-C₄) alkoxy or phenyl, (ii) (C₂-C₄) alkenyl optionallysubstituted with one or more C(═O)(C₁-C₄) alkyl, (iii) (C(R₁₂)₂)_(r)OH,(iv) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (v) C(═O)OH, (vi) C(═O)O(C₁-C₄) alkyl, (vii)C(═O)NR₁₃R₁₅, (viii) C(═O)R₁₆, (ix) S(O)_(p)R₁₆, or (x) 5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S andoptionally substituted with one or more (C₁-C₄) alkyl, (xi) or two R₅together with the carbon atom to which they are attached form (═O), or(xii) two R₅ together with the atoms to which they are attached form abridged 3- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatomsselected from N, O, and S;

R₆ is H or (C₁-C₄) alkyl;

R₇ is H, (C₁-C₄) alkyl, or C(═O)R₂₄;

each R₈ is independently (i) H, (ii) (C₁-C₄) alkyl, or (iii) 5- or6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S and optionally substituted with one or more (C₁-C₄) alkyl, or(iv) two R₈ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl ring comprising 0 to 1 additionalheteroatoms selected from N, O, and S and optionally substituted withone or more (C₁-C₄) alkyl;

R₉ is H or (C₁-C₄) alkyl;

R₁₀ is (C₁-C₄) alkyl or (C₆-C₁₀) aryl;

R₁₁ is (C₃-C₇) cycloalkyl, (C₄-C₇) cycloalkenyl, (C₆-C₁₀) aryl, or 5- or6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O,and S, wherein the aryl and heteroaryl are optionally substituted withone or more R₁₇;

each R₁₂ is independently H or (C₁-C₆) alkyl;

R₁₃ is H or (C₁-C₄) alkyl;

R₁₄ is (i) H, (ii) (C₁-C₄) alkyl, (iii) (C(R₁₈)₂)_(r)C(═O)NR₁₉R₂₀, (iv)(CH₂)_(n)(C₆-C₁₀) aryl optionally substituted with one or more (C₁-C₄)alkyl or halogen, (v) C(═O)R₂₁, (vi) C(═O)O(C₁-C₄) alkyl, (vii)S(O)₂(C₁-C₈) alkyl, (viii) S(O)₂NH(C₁-C₈) alkyl, (ix) S(O)₂N((C₁-C₈)alkyl)₂, or (x) C(═O)(C₁-C₈) alkyl optionally substituted with one ormore R₂₂; or

R₁₃ and R₁₄ together with the nitrogen atom to which they are attachedform a 4- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatomsselected from N, O, and S and optionally substituted with one or moresubstituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, OH, NH₂, and(═O);

R₁₅ is (i) H, (ii) 5- or 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S, or (iii) (C₁-C₄) alkyl optionallysubstituted with one or more substituents selected from OH, 5- or6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S; or

R₁₃ and R₁₅ together with the nitrogen atom to which they are attachedform a 4- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatomsselected from N, O, and S and optionally substituted with one or moresubstituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and OH, orform a 5- to 8-membered bicyclic heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S and optionally substituted withone or more substituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,and OH;

R₁₆ is (C₁-C₄) alkyl, (C₂-C₄) alkenyl, (C₂-C₄) alkynyl, or 3- to6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S, wherein the alkyl, alkenyl, and alkynyl are optionallysubstituted with one or more substituents selected from (C₁-C₄) alkoxy,O-phenyl, halogen, CN, NH₂, (C₁-C₄) alkylamino, di-(C₁-C₄) alkylamino,and OS(O)₂(C₁-C₄) alkyl, and wherein the heterocyclyl is optionallysubstituted with one or more R₂₃;

each R₁₇ is independently (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(═O)NH₂, C(═O)NH(C₁-C₄) alkyl,or C(═O)N((C₁-C₄) alkyl)₂;

each R₁₈ is independently H or (C₁-C₄) alkyl;

R₁₉ is H or (C₁-C₄) alkyl;

R₂₀ is H or (CH₂)_(n)(C₆-C₁₀) aryl optionally substituted with one ormore (C₁-C₄) alkyl;

R₂₁ is (C₃-C₇) cycloalkyl, 5- or 6-membered heterocyclyl comprising 1 to3 heteroatoms selected from N, O, and S, (C₆-C₁₀) aryl, or 5- or6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O,and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl areoptionally substituted with one or more substituents selected from(C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy,OH, and halogen;

each R₂₂ is independently (i) (C₁-C₄) alkoxy, (ii) OH, (iii) NH₂, (iv)(C₁-C₄) alkylamino, (v) di-(C₁-C₄) alkylamino, or (vi) 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S andoptionally substituted with one or more substituents selected from (a)(C₁-C₄) alkyl, (b) (CH₂)_(x)(C₆-C₁₀) aryl, and (c) C(═O)(C₆-C₁₀)aryloptionally substituted with one or more (C₁-C₄) alkyl;

each R₂₃ is independently (C₁-C₄) alkyl or C(═O)(C₁-C₄) alkyl, or twoR₂₃ together with the atoms to which they are attached form a 5- or6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected fromN, O, and S;

R₂₄ is (C₁-C₄) alkyl optionally substituted with one or moresubstituents selected from (C₁-C₄) alkoxy and 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S;

R₂₅ is (C₁-C₄) alkyl optionally substituted with one or more (C₁-C₄)alkoxy, (C(R₂₆)₂)_(x)(C₆-C₁₀) aryl, (C(R₂₆)₂)_(x)-heteroaryl, whereinthe heteroaryl comprises one or two 5- or 6-membered rings and 1 to 3heteroatoms selected from N, O, and S, or (C(R₂₆)₂)_(x)-heterocyclyl,wherein the heterocyclyl comprises one or two 4- to 6-membered rings and1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, alkoxy,aryl, heteroaryl, and heterocyclyl are optionally substituted with oneor more substituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, cyano, halogen, OH, NH₂, (C₆-C₁₀)aryl, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S;

each R₂₆ is independently H or (C₁-C₄) alkyl, or two R₂₆ together withthe atom to which they are attached form a (C₃-C₆) cycloalkyl ring or 3-or 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selectedfrom N, O, and S;

each n and each p is independently 0, 1, or 2;

each r is independently 0, 1, 2, or 3;

each q and each x is independently 0, 1, 2, or 3; and

provided that when R₄ is NR₉S(O)_(p)R₁₀, A is optionally substitutedwith one additional R₄; and

provided that the compound is not(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.

In some embodiments, the compounds of Formula (I) have the structure ofFormula (Ia) or (Ia′):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof.

In some embodiments, the compounds of Formula (I) have the structure ofFormula (Ib) or (Ib′):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof.

In some embodiments, the compounds of Formula (I) have the structure ofFormula (Ic) or (Ic′):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof.

In some embodiments, the compounds of Formula (I) have the structure ofFormula (Id) or (Id′):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof.

In some embodiments, the compounds of Formula (I) have the structure ofFormula (Ie) or (Ie′):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof.

In some embodiments, the compounds of Formula (I) have the structure ofFormula (If) or (If):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof.

In some embodiments, the compounds of Formula (I) have the structure anyof Formulae (Ig1) and (Ig12):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof.

In some embodiments, the compounds of Formula (I) have the structure anyof Formulae (Ih1) and (Ih12):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof.

In some embodiments, the compounds of Formula (I) have the structure anyof Formulae (Ii1) and (Ii12):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof.

In some embodiments of the formulae above, A is (C₆-C₁₀) aryl optionallysubstituted with one or more R₄. In one embodiment, A is 5- or6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O,and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, and furanyl), optionally substituted with one or more R₄. Inanother embodiment, A is 5-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, and furanyl), optionally substituted with one or more R₄. Inanother embodiment, A is 6-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyridinyl, pyrazinyl, andpyrimidinyl), optionally substituted with one or more R₄. In anotherembodiment, A is (C₆-C₁₀) aryl or 5-membered heteroaryl comprising 1 to3 heteroatoms selected from N, O, and S, wherein each is optionallysubstituted with one or more R₄. In another embodiment, A is (C₆-C₁₀)aryl or 6-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom N, O, and S, wherein each is optionally substituted with one ormore R₄.

In another embodiment, A is phenyl, thiophenyl, or pyridinyl whereineach is optionally substituted with one or more R₄. In anotherembodiment, A is phenyl, thiophenyl, or pyridinyl wherein each issubstituted with one or more R₄. In another embodiment, A is phenyl,thiophenyl, or pyridinyl. In another embodiment, A is phenyl optionallysubstituted with one to two R₄. In another embodiment, A is phenylsubstituted with one to two R₄. In another embodiment, A is phenyl. Inanother embodiment, A is thiophenyl optionally substituted with one totwo R₄. In another embodiment, A is thiophenyl substituted with one totwo R₄. In another embodiment, A is thiophenyl. In another embodiment, Ais pyridinyl optionally substituted with one to two R₄. In anotherembodiment, A is pyridinyl substituted with one to two R₄. In anotherembodiment, A is pyridinyl. In a further embodiment, A is phenyl,thiophenyl, or pyridinyl wherein each is optionally substituted with oneto two R₄. In another further embodiment, A is phenyl, thiophenyl, orpyridinyl wherein each is substituted with one to two R₄.

In some embodiments of the formulae above, each R₄ is independently(C₁-C₄) alkyl, (C₁-C₄) alkoxy optionally substituted with one or more(C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen,NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁, C(═O)NHR₂₅, NHC(═O)R₂₅, or heterocyclylcomprising one or two 4- to 6-membered rings and 1 to 3 heteroatomsselected from N, O, and S and optionally substituted with one or moresubstituents selected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,C(═O)(C₁-C₄) alkyl, and halogen.

In some embodiments of the formulae above, each R₄ is independently(C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy,halogen, or O(CH₂)_(n)R₁₁, wherein the alkoxy is optionally substitutedwith one or more (C₁-C₄) alkoxy.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl). In another embodiment, at least one R₄ is methyl, ethyl,n-propyl, or i-propyl. In another embodiment, at least one R₄ is methylor ethyl. In another embodiment, at least one R₄ is methyl.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,or t-butoxy) optionally substituted with one or more (C₁-C₄) alkoxy(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, ort-butoxy). In another embodiment, at least one R₄ is methoxy or ethoxy,wherein each is optionally substituted with one or more (C₁-C₄) alkoxy(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, ort-butoxy). In another embodiment, at least one R₄ is methoxy or ethoxy,wherein each is optionally substituted with one or more methoxy orethoxy. In another embodiment, at least one R₄ is methoxy or ethoxy,wherein each is optionally substituted with one to two methoxy. In afurther embodiment, at least one R₄ is methoxy or ethoxy, wherein eachis optionally substituted with one methoxy.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl,etc.). In a further embodiment, at least one R₄ is CF₃.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)haloalkoxy (e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃, OCCl₃, OCHCl₂,OCH₂Cl, etc.).

In some embodiments of the formulae above, at least one R₄ is halogen(e.g., F, Cl, Br, or I). In another embodiment, at least one R₄ is F orCl. In another embodiment, at least one R₄ is F. In another embodiment,at least one R₄ is Cl.

In some embodiments of the formulae above, at least one R₄ is OR₁₁,O(CH₂)R₁₁, or O(CH₂)₂R₁₁. In another embodiment, at least one R₄ is OR₁₁or O(CH₂)R₁₁.

In some embodiments of the formulae above, at least one R₄ is NHR₁₁,NH(CH₂)R₁₁, or NH(CH₂)₂R₁₁. In another embodiment, at least one R₄ isNHR₁₁ or NH(CH₂)R₁₁.

In some embodiments of the formulae above, at least one R₄ isC(═O)NHR₂₅, (CH₂)C(═O)NHR₂₅, or (CH₂)₂C(═O)NHR₂₅. In another embodiment,at least one R₄ is C(═O)NHR₂₅ or (CH₂)C(═O)NHR₂₅.

In some embodiments of the formulae above, at least one R₄ isNHC(═O)R₂₅, (CH₂)NHC(═O)R₂₅, or (CH₂)₂NHC(═O)R₂₅. In another embodiment,at least one R₄ is NHC(═O)R₂₅ or (CH₂)NHC(═O)R₂₅.

In some embodiments of the formulae above, at least one R₄ isNHC(═O)NHR₂₅, (CH₂)NHC(═O)NHR₂₅, or (CH₂)₂NHC(═O)NHR₂₅. In anotherembodiment, at least one R₄ is NHC(═O)NHR₂₅ or (CH₂)NHC(═O)NHR₂₅.

In some embodiments of the formulae above, at least one R₄ is(CH₂)C(═O)NHR₂₅, (CH₂)NHC(═O)NHR₂₅, or (CH₂)NHC(═O)NHR₂₅.

In some embodiments of the formulae above, at least one R₄ isCH₂)C(═O)NHR₂₅ or (CH₂)NHC(═O)NHR₂₅.

In some embodiments of the formulae above, at least one R₄ isCH₂)NHC(═O)NHR₂₅.

In some embodiments of the formulae above, at least one R₄ is (i)(C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl), (ii) (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) optionallysubstituted with one or more (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), (iii) (C₁-C₄)haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl,etc.), (iv) (C₁-C₄) haloalkoxy (e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCF₂CF₃, OCCl₃, OCHCl₂, OCH₂Cl, etc.), (v) halogen (e.g., F, Cl, Br, orI), (vi) NR₉S(O)_(p)R₁₀, (vii) O(CH₂)_(n)R₁₁, (viii) NH(CH₂)_(n)R₁₁,(ix) (CH₂)_(n)C(═O)NHR₂₅, (x) (CH₂)_(n)NHC(═O)R₂₅, (xi)(CH₂)_(n)NHC(═O)NHR₂₅, (xii) C(═O)R₂₅, or (xiii) heterocyclyl comprisingone or two 4- to 6-membered rings and 1 to 3 heteroatoms selected fromN, O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl,dioxanyl, and a spiroheterocyclyl such as oxaazaspiro[3.3]heptanyl) andoptionally substituted with one to three substituents selected from(C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl), (C₁-C₄) haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃,CF₂CF₃, CCl₃, CHCl₂, CH₂Cl, etc.), C(═O)(C₁-C₄) alkyl (wherein (C₁-C₄)alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), and halogen (e.g., F, Cl, Br, or I). In another embodiment, atleast one R₄ is (i) O(CH₂)_(n)R₁₁, (ii) NH(CH₂)_(n)R₁₁, (iii)(CH₂)_(n)C(═O)NHR₂₅, (iv) (CH₂)_(n)NHC(═O)R₂₅, (v)(CH₂)_(n)NHC(═O)NHR₂₅, (vi) C(═O)R₂₅, or (vii) heterocyclyl comprisingone or two 4- to 6-membered rings and 1 to 3 heteroatoms selected fromN, O, and S and optionally substituted with one to three substituentsselected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, C(═O)(C₁-C₄) alkyl, andhalogen. In another embodiment, at least one R₄ is heterocyclylcomprising one or two 4- to 6-membered rings and 1 to 3 heteroatomsselected from N, O, and S and optionally substituted with one to threesubstituents selected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,C(═O)(C₁-C₄) alkyl, and halogen.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, or t-butoxy) optionally substituted with one to two(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy), (C₁-C₄) haloalkyl (e.g., CF₃, CHF₂, CH₂F,CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl, etc.), (C₁-C₄) haloalkoxy (e.g.,OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃, OCCl₃, OCHCl₂, OCH₂Cl, etc.),halogen (e.g., F, Cl, Br, or I), NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁,NH(CH₂)_(n)R₁₁, (CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅,(CH₂)_(n)NHC(═O)NHR₂₅, C(═O)R₂₅, or heterocyclyl comprising one or two4- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S(e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl,dioxanyl, and spiroheterocyclyl such as oxaazaspiro[3.3]heptanyl) andoptionally substituted with one or more substituents selected from(C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl). In another embodiment, at least one R₄ is (C₁-C₄)alkyl, (C₁-C₄) alkoxy optionally substituted with one to two (C₁-C₄)alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, orO(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁, (CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅,(CH₂)_(n)NHC(═O)NHR₂₅, C(═O)R₂₅, or 5- or 6-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S and optionallysubstituted with one or more (C₁-C₄) alkyl.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, or t-butoxy), (C₁-C₄) haloalkyl (e.g., CF₃, CHF₂,CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl, etc.), (C₁-C₄) haloalkoxy(e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃, OCCl₃, OCHCl₂, OCH₂Cl,etc.), halogen (e.g., F, Cl, Br, or I), O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁,(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅, orC(═O)R₂₅, wherein the alkoxy is optionally substituted with one or more(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy). In another embodiment, at least one R₄ is(C₁-C₂) alkyl (i.e., methyl or ethyl), (C₁-C₂) alkoxy (i.e., methoxy orethoxy), (C₁-C₂) haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃,CHCl₂, CH₂Cl, etc.), (C₁-C₂) haloalkoxy (e.g., OCF₃, OCHF₂, OCH₂F,OCH₂CF₃, OCF₂CF₃, OCCl₃, OCHCl₂, OCH₂Cl, etc.), halogen (e.g., F, Cl,Br, or I), NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁,(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅, orC(═O)R₂₅, wherein the alkoxy is optionally substituted with one or more(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy). In another embodiment, at least one R₄ is(C₁-C₂) alkyl, (C₁-C₂) alkoxy, (C₁-C₂) haloalkyl, (C₁-C₂) haloalkoxy,halogen, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁, (CH₂)_(n)C(═O)NHR₂₅,(CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅, or C(═O)R₂₅, wherein thealkoxy is optionally substituted with one or more (C₁-C₄) alkoxy. Inanother embodiment, at least one R₄ is methyl, F, Cl, methoxy,OCH₂CH₂OCH₃, NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁,(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NIHC(═O)R₂₅, (CH₂)_(n)NIHC(═O)NHR₂₅, orC(═O)R₂₅. In another embodiment, at least one R₄ is methyl, F, Cl,methoxy, OCH₂CH₂OCH₃, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁,(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NIHC(═O)R₂₅, (CH₂)_(n)NIHC(═O)NHR₂₅,C(═O)R₂₅. In a further embodiment, at least one R₄ is methyl, fluoro,chloro, methoxy, OCH₂CH₂OCH₃, OR₁₁, or O(CH₂)R₁₁, NHR₁₁, NH(CH₂)R₁₁,C(═O)NHR₂₅, (CH₂)C(═O)NHR₂₅, NHC(═O)R₂₅, (CH₂)NHC(═O)R₂₅, NHC(═O)NHR₂₅,(CH₂)NHC(═O)NHR₂₅, or C(═O)R₂₅.

In some embodiments of the formulae above, R₉ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). Inanother embodiment, R₉ is H or (C₁-C₃) alkyl (e.g., methyl, ethyl,n-propyl, or i-propyl). In another embodiment, R₉ is H, methyl, orethyl. In another embodiment, R₉ is H or methyl. In a furtherembodiment, R₉ is H.

In some embodiments of the formulae above, R₁₀ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, n-propyl, or i-propyl) or (C₆-C₁₀) aryl. In anotherembodiment, R₁₀ is (C₁-C₃) alkyl (e.g., methyl, ethyl, n-propyl, ori-propyl) or phenyl. In another embodiment, R₁₀ is methyl, ethyl, orphenyl. In a further embodiment, R₁₀ is methyl or phenyl

In some embodiments of the formulae above, R₁₁ is (C₃-C₇) cycloalkyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl)or (C₄-C₇) cycloalkenyl (e.g., cyclobutenyl, cyclopentenyl,cyclohexenyl, or cycloheptenyl). In another embodiment, R₁₁ is (C₆-C₁₀)aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl), wherein the aryland heteroaryl are optionally substituted with one or more R₁₇. Inanother embodiment, R₁₁ is (C₆-C₁₀) aryl or 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S, wherein thearyl and heteroaryl are optionally substituted with one to three R₁₇. Inanother embodiment, R₁₁ is (C₄-C₇) cycloalkenyl, (C₆-C₁₀) aryl, or 5- or6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O,and S, wherein the aryl and heteroaryl are optionally substituted withone to three R₁₇. In another embodiment, R₁₁ is (C₄-C₇) cycloalkenyl,phenyl, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S, wherein the phenyl and heteroaryl areoptionally substituted with one to three R₁₇.

In another embodiment, R₁₁ is (C₄-C₇) cycloalkenyl (e.g., cyclobutenyl,cyclopentenyl, cyclohexenyl, or cycloheptenyl), phenyl, or 5-memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S(e.g., pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl),wherein the phenyl and heteroaryl are optionally substituted with one tothree R₁₇. In another embodiment, R₁₁ is (C₄-C₇) cycloalkenyl, phenyl,or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., pyridinyl, pyrazinyl, and pyrimidinyl), wherein thephenyl and heteroaryl are optionally substituted with one to three R₁₇.In another embodiment, R₁₁ is phenyl or 5-membered heteroaryl comprising1 to 3 heteroatoms selected from N, O, and S, wherein the phenyl andheteroaryl are optionally substituted with one to three R₁₇. In anotherembodiment, R₁₁ is phenyl or 6-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S, wherein the phenyl and heteroarylare optionally substituted with one to three R₁₇. In another embodiment,R₁₁ is phenyl optionally substituted with one to three R₁₇. In anotherembodiment, R₁₁ is (C₄-C₇) cycloalkenyl, phenyl, or pyridinyl, whereinthe phenyl and pyridinyl are optionally substituted with one to threeR₁₇. In a further embodiment, R₁₁ is cycloalkenyl, phenyl, or pyridinyl,wherein the phenyl and pyridinyl are optionally substituted with one tothree R₁₇. In another embodiment, R₁₁ is phenyl or pyridinyl, whereinthe phenyl and pyridinyl are optionally substituted with one to threeR₁₇.

In some embodiments of the formulae above, each R₁₇ is independentlyC(═O)NH₂, C(═O)NH(C₁-C₄) alkyl (wherein (C₁-C₄) alkyl is methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), or C(═O)N((C₁-C₄)alkyl)₂ (wherein (C₁-C₄) alkyl is methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl).

In some embodiments of the formulae above, at least one R₁₇ is (C₁-C₃)alkyl (e.g., methyl, ethyl, n-propyl, or i-propyl), (C₁-C₃) alkoxy(e.g., methoxy, ethoxy, n-propoxy, or i-propoxy), (C₁-C₃) haloalkyl(e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl, etc.),(C₁-C₃) haloalkoxy (e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃, OCCl₃,OCHCl₂, OCH₂Cl, etc.), or halogen (e.g., F, Cl, Br, or I). In anotherembodiment, at least one R₁₇ is (C₁-C₃) alkyl or (C₁-C₃) alkoxy. Inanother embodiment, at least one R₁₇ is (C₁-C₃) haloalkyl, (C₁-C₃)haloalkoxy, or halogen. In another embodiment, at least one R₁₇ is(C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. In another embodiment, atleast one R₁₇ is methyl, ethyl, F, Cl, methoxy, ethoxy, CF₃, or OCF₃. Inanother embodiment, at least one R₁₇ is methyl, ethyl, F, Cl, or CF₃. Ina further embodiment, at least one R₁₇ is methyl, F, Cl, or CF₃.

In some embodiments of the formulae above, R₂₅ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl)optionally substituted with one or more (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), whereinthe alkyl and alkoxy are optionally substituted with one or moresubstituents selected from (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), (C₁-C₄)haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl,etc.), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, or t-butoxy), (C₁-C₄) haloalkyl (e.g., CF₃, CHF₂,CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl, etc.), (C₁-C₄) haloalkoxy(e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃, OCCl₃, OCHCl₂, OCH₂Cl,etc.), cyano, halogen (e.g., F, Cl, Br, or I), OH, NH₂, (C₆-C₁₀) aryl,and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, and furanyl). In some embodiments of theformulae above, R₂₅ is methyl or ethyl optionally substituted withmethoxy or ethoxy, each of which is optionally substituted.

In some embodiments of the formulae above, R₂₅ is (C(R₂₆)₂)_(x)(C₆-C₁₀)aryl, (C(R₂₆)₂)_(x)-heteroaryl, wherein the heteroaryl comprises one ortwo 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O,and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, and isoquinolinyl), or (C(R₂₆)₂)_(x)-heterocyclyl,wherein the heterocyclyl comprises one or two 4- to 6-membered rings and1 to 3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuryl, dioxanyl, tetrahydroisoquinolinyl,and a spiroheterocyclyl such as oxaazaspiro[3.3]heptanyl), wherein thearyl, heteroaryl, and heterocyclyl are optionally substituted with oneto three substituents selected from (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), (C₁-C₄) alkoxy (e.g.,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy),(C₁-C₄) haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂,CH₂Cl, etc.), (C₁-C₄) haloalkoxy (e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃,OCF₂CF₃, OCCl₃, OCHCl₂, OCH₂Cl, etc.), cyano, halogen (e.g., F, Cl, Br,or I), OH, NH₂, (C₆-C₁₀) aryl, and 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,and furanyl).

In another embodiment, R₂₅ is (C₆-C₁₀) aryl, (C(R₂₆)₂)(C₆-C₁₀) aryl, or(C(R₂₆)₂)₂(C₆-C₁₀) aryl, wherein the aryl is optionally substituted withone to three substituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, cyano, halogen, OH, and NH₂. Inanother embodiment, R₂₅ is (C₆-C₁₀)-heteroaryl, (C(R₂₆)₂)-heteroaryl, or(C(R₂₆)₂)₂-heteroaryl, wherein the heteroaryl is optionally substitutedwith one to three substituents selected from (C₁-C₄) alkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, cyano, halogen, OH, andNH₂. In another embodiment, R₂₅ is (C₆-C₁₀)-heteroaryl,(C(R₂₆)₂)-heteroaryl, or (C(R₂₆)₂)₂-heteroaryl, wherein the heteroarylis 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl) andoptionally substituted with one to three substituents selected from(C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy,cyano, halogen, OH, and NH₂. In another embodiment, R₂₅ is(C₆-C₁₀)-heteroaryl, (C(R₂₆)₂)-heteroaryl, or (C(R₂₆)₂)₂-heteroaryl,wherein the heteroaryl is 6-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyridinyl, pyrazinyl, andpyrimidinyl) and optionally substituted with one to three substituentsselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, cyano, halogen, OH, and NH₂. In another embodiment, R₂₅ is(C₆-C₁₀)-heterocyclyl, (C(R₂₆)₂)-heterocyclyl, or(C(R₂₆)₂)₂-heterocyclyl optionally substituted with one to threesubstituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, cyano, halogen, OH, and NH₂. In anotherembodiment, R₂₅ is phenyl or pyridinyl comprising 1 to 3 heteroatomsselected from N, O, and S, and optionally substituted with one to threesubstituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, cyano, halogen, OH, and NH₂. In anotherembodiment, R₂₅ is phenyl or pyridinyl comprising 1 to 3 heteroatomsselected from N, O, and S, and optionally substituted with one to threehalogen.

In some embodiments of the formulae above, each R₂₆ is H.

In some embodiments of the formulae above, at least one R₂₆ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl).

In some embodiments of the formulae above, two R₂₆ together with theatom to which they are attached form a (C₃-C₆) cycloalkyl ring (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or 3- or 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxiranyl, aziridinyl,oxetanyl, azetidinyl, and thietanyl). In another embodiment, two R₂₆together with the atom to which they are attached form a cyclopropyl orcyclobutyl ring, or 3- or 4-membered heterocyclyl ring comprising 1 or 2heteroatoms selected from N, O, and S (e.g., oxiranyl, aziridinyl,oxetanyl, azetidinyl, and thietanyl).

In some embodiments of the formulae above, R₁ is (C₃-C₇) cycloalkyloptionally substituted with one or more R₅. In another embodiment, R₁ iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyloptionally substituted with one to three R₅. In another embodiment, R₁is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl optionallysubstituted with one to three R₅. In another embodiment, R₁ iscyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl substituted with oneto three R₅. In another embodiment, R₁ is cyclopropyl optionallysubstituted with one to three R₅. In another embodiment, R₁ iscyclopropyl substituted with one to three R₅. In another embodiment, R₁is cyclobutyl optionally substituted with one to three R₅. In anotherembodiment, R₁ is cyclobutyl substituted with one to three R₅. Inanother embodiment, R₁ is cyclopentyl optionally substituted with one tothree R₅. In another embodiment, R₁ is cyclopentyl substituted with oneto three R₅. In another embodiment, R₁ is cyclohexyl optionallysubstituted with one to three R₅. In another embodiment, R₁ iscyclohexyl substituted with one to three R₅. In another embodiment, R₁is cycloheptyl optionally substituted with one to three R₅. In anotherembodiment, R₁ is cycloheptyl substituted with one to three R₅.

In another embodiment, R₁ is 4- to 6-membered heterocyclyl comprising 1to 3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl,dioxanyl, oxetanyl, azetidinyl, and thietanyl), optionally substitutedwith one or more R₅. In another embodiment, R₁ is 4-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S(e.g., oxetanyl, azetidinyl, and thietanyl), optionally substituted withone or more R₅. In another embodiment, R₁ is 5-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,[1,3]dioxolanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl), optionally substituted with oneor more R₅. In another embodiment, R₁ is 6-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl),optionally substituted with one or more R₅. In another embodiment, R₁ ispiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or1,4-dioxanyl optionally substituted with one or more R₅. In anotherembodiment, R₁ is piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,pyrrolidinyl, or 1,4-dioxanyl optionally substituted with one to threeR₅. In another embodiment, R₁ is piperidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyl substituted with one tothree R₅. In another embodiment, R₁ is piperidinyl optionallysubstituted with one to three R₅. In another embodiment, R₁ istetrahydrofuranyl optionally substituted with one to three R₅. Inanother embodiment, R₁ is tetrahydropyranyl optionally substituted withone to three R₅. In another embodiment, R₁ is pyrrolidinyl optionallysubstituted with one to three R₅. In another embodiment, R₁ is1,4-dioxanyl optionally substituted with one to three R₅. In a furtherembodiment, R₁ is cyclohexyl, cyclopentyl, cyclobutyl, tetrahydropyran,tetrahydrofuran, piperidinyl, 1,4-dioxane, pyrrolyl, or cyclohexanonewherein each substituted with one to two R₅.

In some embodiments of the formulae above, at least one R₅ is (i)(C₁-C₆) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one tothree (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, or t-butoxy) or phenyl, (ii) (C₂-C₄) alkenyl (e.g.,ethenyl, propenyl, or butenyl) optionally substituted with one or moreC(═O)(C₁-C₄) alkyl (wherein (C₁-C₄) alkyl is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl), (iii) (C(R₁₂)₂)_(r)OH, (iv)(C(R₁₂)₂)_(r)NR₁₃R₁₄, (v) C(═O)OH, (vi) C(═O)O(C₁-C₄) alkyl (wherein(C₁-C₄) alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (vii) C(═O)NR₁₃R₁₅, (viii) C(═O)R₁₆, (ix) S(O)_(p)R₁₆, or (x)5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected fromN, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, and furanyl) and optionally substituted withone to three (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl), (xi) or two R₅ together with the carbonatom to which they are attached form (═O), or (xii) two R₅ together withthe atoms to which they are attached form a bridged 3- to 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl,dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, andthiiranyl). In another embodiment, at least one R₅ is (i) (C₁-C₆) alkyloptionally substituted with one to three (C₁-C₄) alkoxy or phenyl, (ii)(C₂-C₄) alkenyl optionally substituted with one or more C(═O)(C₁-C₄)alkyl, (iii) (C(R₁₂)₂)_(r)OH, (iv) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (v) C(═O)OH,(vi) C(═O)O(C₁-C₄) alkyl, (vii) C(═O)NR₁₃R₁₅, (viii) C(═O)R₁₆, (ix)S(O)_(p)R₁₆, or (x) 5- or 6-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S and optionally substituted withone to three (C₁-C₄) alkyl, (xi) or two R₅ together with the carbon atomto which they are attached form (═O). In another embodiment, at leastone R₅ is (i) (C₂-C₄) alkenyl optionally substituted with one or moreC(═O)(C₁-C₄) alkyl, (ii) (C(R₁₂)₂)_(r)OH, (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄,(iv) C(═O)O(C₁-C₄) alkyl, (v) C(═O)NR₁₃R₁₅, (vi) C(═O)R₁₆, or (vii)S(O)_(p)R₁₆. In another embodiment, at least one R₅ is (i) (C₂-C₄)alkenyl optionally substituted with one or more C(═O)(C₁-C₄) alkyl or(ii) S(O)_(p)R₁₆.

In some embodiments of the formulae above, at least one R₅ is (i)(C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl) optionally substituted with one to two (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,or t-butoxy) or phenyl, (ii) (C(R₁₂)₂)_(r)OH, (iii)(C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv) C(═O)OH, (v) C(═O)O(C₁-C₄) alkyl (wherein(C₁-C₄) alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (vi) C(═O)NR₁₃R₁₅, (vii) C(═O)R₁₆, (viii) S(O)_(p)R₁₆, or (ix)5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected fromN, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, and furanyl) and optionally substituted withone or more (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl), or (x) two R₅ together with the carbonatom to which they are attached form (═O), or (xi) two R₅ together withthe atoms to which they are attached form a bridged 3- to 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl,dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, andthiiranyl). In another embodiment, R₅ is independently (i) (C₁-C₄) alkyloptionally substituted with one to two (C₁-C₄) alkoxy or phenyl, (ii)(C(R₁₂)₂)_(r)OH, (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv) C(═O)O(C₁-C₄) alkyl,(v) C(═O)NR₁₃R₁₅, (vi) C(═O)R₁₆, or (vii) S(O)_(p)R₁₆. In anotherembodiment, (i) two R₅ together with the carbon atom to which they areattached form (═O), or (ii) two R₅ together with the atoms to which theyare attached form a bridged 3- to 6-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S.

In some embodiments of the formulae above, at least one R₅ is (i)(C₁-C₃) alkyl (e.g., methyl, ethyl, n-propyl, or i-propyl) optionallysubstituted with one to three (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) or phenyl, (ii)(C(R₁₂)₂)_(r)OH, (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv) C(═O)OH, (v)C(═O)O(C₁-C₄) alkyl (wherein (C₁-C₄) alkyl is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl), (vi) C(═O)NR₁₃R₁₅, (vii)C(═O)R₁₆, or (viii) 5- or 6-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl), andoptionally substituted with one or more (C₁-C₄) alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In anotherembodiment, at least one R₅ is (i) (C₁-C₃) alkyl optionally substitutedwith one to three (C₁-C₄) alkoxy or phenyl, (ii) (C(R₁₂)₂)_(r)OH, (iii)(C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv) C(═O)OH, (v) C(═O)O(C₁-C₄) alkyl, (vi)C(═O)NR₁₃R₁₅, (vii) C(═O)R₁₆, (viii) 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S and optionallysubstituted with one or more (C₁-C₄) alkyl, or (ix) two R₅ together withthe carbon atom to which they are attached form (═O). In anotherembodiment, at least one R₅ is (i) (C₁-C₂) alkyl (i.e., methyl or ethyl)optionally substituted with one to three (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) orphenyl, (ii) (C(R₁₂)₂)_(r)OH, or (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄. In anotherembodiment, at least one R₅ is (i) C(═O)OH, (ii) C(═O)O(C₁-C₄) alkyl,(iii) C(═O)NR₁₃R₁₅, or (iv) C(═O)R₁₆. In another embodiment, at leastone R₅ is (i) (C(R₁₂)₂)_(r)OH, (ii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iii)C(═O)NR₁₃R₁₅, or (iv) C(═O)R₁₆. In another embodiment, at least one R₅is (i) (C₁-C₂) alkyl optionally substituted with one to three (C₁-C₄)alkoxy or phenyl, (ii) (C(R₁₂)₂)_(r)OH, (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv)C(═O)O(C₁-C₄) alkyl, or (v) C(═O)NR₁₃R₁₅. In another embodiment, atleast one R₅ is (i) (C₁-C₂) alkyl optionally substituted with one tothree (C₁-C₄) alkoxy or phenyl, (ii) (C(R₁₂)₂)_(r)OH, (iii)(C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv) C(═O)NR₁₃R₁₅, (v) C(═O)R₁₆.

In another embodiment, at least one R₅ is (i) C(═O)OH, (ii)C(═O)O(C₁-C₄) alkyl (wherein (C₁-C₄) alkyl is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl), (iii) C(═O)NR₁₃R₁₅, or (iv)C(═O)R₁₆. In another embodiment, at least one R₅ is (i) (C(R₁₂)₂)_(r)OH,(ii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iii) C(═O)NR₁₃R₁₅, or (iv) C(═O)R₁₆. Inanother embodiment, at least one R₅ is (i) (C(R₁₂)₂)_(r)OH, (ii)(C(R₁₂)₂)_(r)NR₁₃R₁₄, (iii) C(═O)NR₁₃R₁₅, (iv) C(═O)R₁₆, or (v) two R₅together with the carbon atom to which they are attached form (═O). Inanother embodiment, at least one R₅ is (i) (C₁-C₂) alkyl (i.e., methylor ethyl) optionally substituted with one to three (C₁-C₄) alkoxy (e.g.,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy)or phenyl, (ii) (C(R₁₂)₂)_(r)OH, (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv)C(═O)O(C₁-C₄) alkyl, or (v) C(═O)NR₁₃R₁₅. In another embodiment, atleast one R₅ is (i) (C₁-C₂) alkyl (i.e., methyl or ethyl) optionallysubstituted with one to three (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) or phenyl, (ii)(C(R₁₂)₂)_(r)OH, (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv) C(═O)NR₁₃R₁₅, or (v)C(═O)R₁₆.

In some embodiments of the formulae above, two R₅ together with thecarbon atom to which they are attached form (═O). In another embodiment,at least one R₅ is (i) (C₁-C₂) alkyl (i.e., methyl or ethyl) optionallysubstituted with one to three (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) or phenyl, (ii)(C(R₁₂)₂)_(r)OH, (iii) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (iv) C(═O)NR₁₃R₁₅, (v)C(═O)R₁₆, or (vi) two R₅ together with the carbon atom to which they areattached form (═O).

In some embodiments of the formulae above, at least one R₁₂ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl). In another embodiment, at least one R₁₂ is H or (C₁-C₃) alkyl(e.g., methyl, ethyl, n-propyl, or i-propyl). In another embodiment, atleast one R₁₂ is H, methyl, or ethyl. In another embodiment, at leastone R₁₂ is H. In a further embodiment, at least one R₁₂ is H or methyl.In another embodiment, each R₁₂ is H.

In some embodiments of the formulae above, R₁₃ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). Inanother embodiment, R₁₃ is H or (C₁-C₃) alkyl (e.g., methyl, ethyl,n-propyl, or i-propyl). In another embodiment, R₁₃ is H, methyl, orethyl. In another embodiment, R₁₃ is H or methyl. In another embodiment,R₁₃ is H.

In some embodiments of the formulae above, R₁₄ is (i) H, (ii) (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (iii) (C(R₁₈)₂)_(r)C(═O)NR₁₉R₂₀, (iv) (CH₂)_(n)(C₆-C₁₀) aryloptionally substituted with one to three (C₁-C₄) alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) or halogen(e.g., F, Cl, Br, or I), (v) C(═O)R₂₁, (vi) C(═O)O(C₁-C₄) alkyl (wherein(C₁-C₄) alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (vii) S(O)₂(C₁-C₈) alkyl (wherein (C₁-C₈) alkyl is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, hexyl, heptyl,octyl), (viii) S(O)₂NH(C₁-C₈) alkyl (wherein (C₁-C₈) alkyl is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, hexyl, heptyl,octyl), (ix) S(O)₂N((C₁-C₈) alkyl)₂, or (x) C(═O)(C₁-C₈) alkyl (wherein(C₁-C₈) alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,t-butyl, hexyl, heptyl, octyl) optionally substituted with one or moreR₂₂. In another embodiment, R₁₄ is (i) S(O)₂(C₁-C₈) alkyl, (ii)S(O)₂NH(C₁-C₈) alkyl, (iii) S(O)₂N((C₁-C₈) alkyl)₂, or (iv) C(═O)(C₁-C₈)alkyl optionally substituted with one or more R₂₂.

In some embodiments of the formulae above, R₁₄ is (i) H, (ii) (C₁-C₂)alkyl (i.e., methyl or ethyl), (iii) (C(R₁₈)₂)_(r)C(═O)NR₁₉R₂₀, (iv)(CH₂)_(n)(C₆-C₁₀) aryl optionally substituted with one to three (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl) or halogen (e.g., F, Cl, Br, or I), (v) C(═O)R₂₁, (vi)C(═O)O(C₁-C₄) alkyl (wherein (C₁-C₄) alkyl is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl), or (viii) C(═O)(C₁-C₈) alkyl(wherein (C₁-C₈) alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, hexyl, heptyl, octyl) optionally substituted with oneor more R₂₂. In another embodiment, R₁₄ is (i) H, (ii) (C₁-C₂) alkyl,(iii) (C(R₁₈)₂)_(r)C(═O)NR₁₉R₂₀, (iv) (CH₂)_(n)(C₆-C₁₀) aryl optionallysubstituted with one to three (C₁-C₄) alkyl or halogen. In anotherembodiment, R₁₄ is (i) H, (ii) (C₁-C₂) alkyl, (iii) C(═O)R₂₁, (iv)C(═O)O(C₁-C₄) alkyl, or (v) C(═O)(C₁-C₈) alkyl optionally substitutedwith one or more R₂₂. In another embodiment, R₁₄ is (i)(C(R₁₈)₂)_(r)C(═O)NR₁₉R₂₀, (ii) (CH₂)_(n)(C₆-C₁₀) aryl optionallysubstituted with one to three (C₁-C₄) alkyl or halogen, (iii) C(═O)R₂₁,(iv) C(═O)O(C₁-C₄) alkyl, or (v) C(═O)(C₁-C₈) alkyl optionallysubstituted with one or more R₂₂. In another embodiment, R₁₄ is (i) H,(ii) (C₁-C₂) alkyl, (iii) (CH₂)_(n)(C₆-C₁₀) aryl optionally substitutedwith one to three (C₁-C₄) alkyl or halogen, (iv) C(═O)R₂₁, (v)C(═O)O(C₁-C₄) alkyl, or (v) C(═O)(C₁-C₈) alkyl optionally substitutedwith one or more R₂₂. In another embodiment, R₁₄ is (i) C(═O)R₂₁, (ii)C(═O)O(C₁-C₄) alkyl, or (iii) C(═O)(C₁-C₈) alkyl optionally substitutedwith one or more R₂₂.

In some embodiments of the formulae above, at least one R₂₂ is (i)(C₁-C₂) alkoxy (i.e., methoxy or ethoxy), (ii) OH, (iii) NH₂, (iv)(C₁-C₂) alkylamino (i.e., methylamino or ethylamino), (v) di-(C₁-C₂)alkylamino (i.e., dimethylamino, methylethylamino or diethylamino), or(vi) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuryl, and dioxanyl) and optionally substituted with one ormore substituents selected from (a) (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), (b) (CH₂)_(x)(C₆-C₁₀)aryl, and (c) C(═O)(C₆-C₁₀)aryl optionally substituted with one or more(C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl). In another embodiment, at least one R₂₂ is (i)(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy), (ii) OH, (iii) NH₂, (iv) (C₁-C₄) alkylamino(e.g., methylamino, ethylamino, propylamino, or butylamino), or (v)di-(C₁-C₄) alkylamino (e.g., dimethylamino, diethylamino, dipropylamino,or dibutylamino). In another embodiment, at least one R₂₂ is 5- or6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S and optionally substituted with one or more substituentsselected from (a) (C₁-C₄) alkyl, (b) (CH₂)_(x)(C₆-C₁₀) aryl, and (c)C(═O)(C₆-C₁₀)aryl optionally substituted with one or more (C₁-C₄) alkyl.

In another embodiment, at least one R₂₂ is (i) (C₁-C₂) alkoxy (i.e.,methoxy or ethoxy), (ii) OH, (iii) di-(C₁-C₂) alkylamino (i.e.,dimethylamino, methylethylamino or diethylamino), or (iv) 5- or6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, anddioxanyl) and optionally substituted with one to two substituentsselected from (a) (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl), (b) (CH₂)_(x)(C₆-C₁₀) aryl, and(c) C(═O)(C₆-C₁₀)aryl optionally substituted with one or more (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl). In another embodiment, at least one R₂₂ is (i) (C₁-C₂) alkoxy,(ii) OH, (iii) di-(C₁-C₂) alkylamino, or (iv) 6-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl)and optionally substituted with one to two substituents selected from(a) (C₁-C₄) alkyl, (b) (CH₂)_(x)(C₆-C₁₀) aryl, and (c) C(═O)(C₆-C₁₀)aryl optionally substituted with one or more (C₁-C₄) alkyl.

In some embodiments of the formulae above, at least one R₁₈ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl). In another embodiment, at least one R₁₈ is H or (C₁-C₃) alkyl(e.g., methyl, ethyl, n-propyl, or i-propyl). In another embodiment, atleast one R₁₈ is H, methyl, or ethyl. In another embodiment, at leastone R₁₈ is H or methyl. In another embodiment, each R₁₈ is H.

In some embodiments of the formulae above, R₁₉ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). Inanother embodiment, R₁₉ is H or (C₁-C₃) alkyl (e.g., methyl, ethyl,n-propyl, or i-propyl). In another embodiment, R₁₉ is H, methyl, orethyl. In another embodiment, R₁₉ is H or methyl. In another embodiment,R₁₉ is H.

In some embodiments of the formulae above, R₂₀ is H or (CH₂)_(n)(C₆-C₁₀)aryl optionally substituted with one to three (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). Inanother embodiment, R₂₀ is H. In another embodiment, R₂₀ is(CH₂)_(n)phenyl optionally substituted with one to three (C₁-C₄) alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl).In another embodiment, R₂₀ is H or (CH₂)_(n)phenyl optionallysubstituted with one to three (C₁-C₄) alkyl.

In some embodiments of the formulae above, R₂₁ is (C₃-C₇) cycloalkyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl), 5- or 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuryl, and dioxanyl), (C₆-C₁₀) aryl, or 5-or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, and furanyl), wherein the aryl, heteroaryl, cycloalkyl, andheterocyclyl are optionally substituted with one to three substituentsselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), (C₁-C₄)haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl,etc.), (C₁-C₄) haloalkoxy (e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃,OCCl₃, OCHCl₂, OCH₂Cl, etc.), OH, and halogen (e.g., F, Cl, Br, or I).In another embodiment, R₂₁ is (C₃-C₇) cycloalkyl or 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three substituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, OH, and halogen. In anotherembodiment, R₂₁ is (C₆-C₁₀) aryl or 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S, wherein thearyl and heteroaryl are optionally substituted with one to threesubstituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, OH, and halogen.

In some embodiments of the formulae above, R₁₆ is (i) (C₁-C₄) alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),(ii) (C₂-C₄) alkenyl (e.g., ethenyl, propenyl, butenyl), (iii) (C₂-C₄)alkynyl (e.g., ethynyl, propynyl, butynyl), or (iv) 3- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S(e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl,dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, andthiiranyl), wherein the alkyl, alkenyl, and alkynyl are optionallysubstituted with one to three substituents selected from (C₁-C₄) alkoxy(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, ort-butoxy), O-phenyl, halogen (e.g., F, Cl, Br, or I), CN, NH₂, (C₁-C₄)alkylamino (e.g., methylamino, ethylamino, propylamino, or butylamino),di-(C₁-C₄) alkylamino (e.g., dimethylamino, diethylamino, dipropylamino,or dibutylamino), and OS(O)₂(C₁-C₄) alkyl (wherein (C₁-C₄) alkyl ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), andwherein the heterocyclyl is optionally substituted with one or more R₂₃.In another embodiment, R₁₆ is (ii) (C₂-C₄) alkenyl, (iii) (C₂-C₄)alkynyl, or (iv) 3- to 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S, wherein the alkenyl and alkynylare optionally substituted with one to three substituents selected from(C₁-C₄) alkoxy, O-phenyl, halogen, CN, NH₂, (C₁-C₄) alkylamino,di-(C₁-C₄) alkylamino, and OS(O)₂(C₁-C₄) alkyl, and wherein theheterocyclyl is optionally substituted with one or more R₂₃. In anotherembodiment, R₁₆ is (ii) (C₂-C₄) alkenyl, (iii) (C₂-C₄) alkynyl, or (iv)3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selectedfrom N, O, and S, wherein the alkenyl, and alkynyl are optionallysubstituted with one to three substituents selected from O-phenyl,halogen, CN, and OS(O)₂(C₁-C₄) alkyl, and wherein the heterocyclyl isoptionally substituted with one or more R₂₃.

In some embodiments of the formulae above, R₁₆ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) or 5-or 6-membered heterocyclyl (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuryl, and dioxanyl) comprising 1 to 3 heteroatoms selectedfrom N, O, and S, wherein the alkyl is optionally substituted with oneto three substituents selected from (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), NH₂,(C₁-C₄) alkylamino (e.g., methylamino, ethylamino, propylamino, orbutylamino), and di-(C₁-C₄) alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), and wherein theheterocyclyl is optionally substituted with one to three R₂₃. In anotherembodiment, R₁₆ is (C₁-C₄) alkyl optionally substituted with one tothree substituents selected from (C₁-C₄) alkoxy, NH₂, (C₁-C₄)alkylamino, and di-(C₁-C₄) alkylamino. In another embodiment, R₁₆ is 5-or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected fromN, O, and S and optionally substituted with one to three R₂₃. In anotherembodiment, R₁₆ is 5-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl) and optionally substituted withone to three R₂₃. In another embodiment, R₁₆ is 6-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl)and optionally substituted with one to three R₂₃.

In another embodiment, R₁₆ is (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) optionally substitutedwith one to three substituents selected from (C₁-C₄) alkoxy (e.g.,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy)and di-(C₁-C₄) alkylamino (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino). In another embodiment, R₁₆ is (C₁-C₄)alkyl optionally substituted with one to three substituents selectedfrom (C₁-C₄) alkoxy and di-(C₁-C₄) alkylamino, or 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S(e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, anddioxanyl) and optionally substituted with one to three R₂₃. In anotherembodiment, R₁₆ is (C₁-C₄) alkyl optionally substituted with one tothree substituents selected from (C₁-C₄) alkoxy and di-(C₁-C₄)alkylamino, or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, and dioxanyl) and optionally substituted with one tothree R₂₃. In another embodiment, R₁₆ is (C₁-C₄) alkyl optionallysubstituted with one to three substituents selected from (C₁-C₄) alkoxy,and di-(C₁-C₄) alkylamino or 5-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl) and optionallysubstituted with one to three R₂₃.

In another embodiment, R₁₆ is (i) (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), (ii) (C₂-C₄) alkenyl(e.g., ethenyl, propenyl, butenyl), (iii) (C₂-C₄) alkynyl (e.g.,ethynyl, propynyl, butynyl), or (iv) 5- or 6-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, and dioxanyl), whereinthe alkyl, alkenyl, and alkynyl are optionally substituted with one tothree substituents selected from (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), CN, NH₂, (C₁-C₄)alkylamino (e.g., methylamino, ethylamino, propylamino, or butylamino),and di-(C₁-C₄) alkylamino (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), and wherein the heterocyclyl isoptionally substituted with one or more R₂₃. In another embodiment, R₁₆is (i) (C₁-C₄) alkyl, (ii) (C₂-C₄) alkenyl, or (iii) (C₂-C₄) alkynyl,wherein the alkyl, alkenyl, and alkynyl are optionally substituted withone to three substituents selected from (C₁-C₄) alkoxy, CN, NH₂, (C₁-C₄)alkylamino, and di-(C₁-C₄) alkylamino. In another embodiment, R₁₆ is (i)(C₂-C₄) alkenyl or (ii) (C₂-C₄) alkynyl, wherein the alkenyl and alkynylare optionally substituted with one to three substituents selected from(C₁-C₄) alkoxy, CN, NH₂, (C₁-C₄) alkylamino, and di-(C₁-C₄) alkylamino.

In some embodiments of the formulae above, at least one R₂₃ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl) or C(═O)(C₁-C₄) alkyl (wherein (C₁-C₄) alkyl is methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In anotherembodiment, at least one R₂₃ is (C₁-C₃) alkyl (e.g., methyl, ethyl,n-propyl, or i-propyl). In another embodiment, at least one R₂₃ ismethyl or ethyl. In another embodiment, each R₂₃ is independentlyC(═O)(C₁-C₄) alkyl or two R₂₃ together with the atoms to which they areattached form a 5- or 6-membered heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl). In anotherembodiment, each R₂₃ is independently C(═O)(C₁-C₄) alkyl.

In some embodiments of the formulae above, two R₂₃ together with theatoms to which they are attached form a 5-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl).In another embodiment, two R₂₃ together with the atoms to which they areattached form a 6-membered heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S (e.g., piperidinyl, piperazinyl,morpholinyl, tetrahydropyranyl, and dioxanyl).

In some embodiments of the formulae above, R₁₃ and R₁₄ together with thenitrogen atom to which they are attached form a 4- to 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl,dioxanyl, oxetanyl, azetidinyl, and thietanyl) optionally substitutedwith one to three substituents selected from (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy), OH, NH₂, and (═O). In another embodiment, R₁₃and R₁₄ together with the nitrogen atom to which they are attached forma 4- or 5-membered heterocyclyl ring comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuryl, oxetanyl, azetidinyl, and thietanyl)optionally substituted with one to three substituents selected from(C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH, NH₂, and (═O). Inanother embodiment, R₁₃ and R₁₄ together with the nitrogen atom to whichthey are attached form a 5- or 6-membered heterocyclyl ring comprising 1to 3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuryl, and dioxanyl) optionally substitutedwith one to three substituents selected from (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy), OH, NH₂, and (═O). In another embodiment, R₁₃and R₁₄ together with the nitrogen atom to which they are attached forma 4-membered heterocyclyl ring comprising 1 to 3 heteroatoms selectedfrom N, O, and S (e.g., oxetanyl, azetidinyl, and thietanyl) optionallysubstituted with one to three substituents selected from (C₁-C₄) alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy), OH, NH₂, and (═O). In another embodiment, R₁₃and R₁₄ together with the nitrogen atom to which they are attached forma 5-membered heterocyclyl ring comprising 1 to 3 heteroatoms selectedfrom N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, andtetrahydrofuryl) optionally substituted with one to three substituentsselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH, NH₂, and(═O). In another embodiment, R₁₃ and R₁₄ together with the nitrogen atomto which they are attached form a 6-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl)optionally substituted with one to three substituents selected from(C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH, NH₂, and (═O).

In some embodiments of the formulae above, R₁₅ is (i) H or (ii) (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl) optionally substituted with one or more substituents selectedfrom OH, 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuryl, and dioxanyl), and 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,and furanyl). In another embodiment, R₁₅ is (i) 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S(e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, anddioxanyl) or (ii) (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl) optionally substituted with oneor more substituents selected from OH, 5- or 6-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, and dioxanyl), and 5-or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, and furanyl). In another embodiment, R₁₅ is (i) H, (ii)6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, and dioxanyl), or (iii) (C₁-C₄) alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) optionallysubstituted with one or more substituents selected from OH, 5- or6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, anddioxanyl), and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl). In anotherembodiment, R₁₅ is (i) H, (ii) 5-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl), or (iii) (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl) optionally substituted with one or more substituents selectedfrom OH, 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuryl, and dioxanyl), and 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,and furanyl). In another embodiment, R₁₅ is H. In another embodiment,R₁₅ is 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S. In another embodiment, R₁₅ is 5-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. Inanother embodiment, R₁₅ is 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S. In another embodiment, R₁₅ is(C₁-C₄) alkyl optionally substituted with one or more substituentsselected from OH, 5- or 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S, and 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S. In anotherembodiment, R₁₅ is (C₁-C₄) alkyl optionally substituted with one or moresubstituents selected from OH, 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S, and 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S. In anotherembodiment, R₁₅ is (C₁-C₄) alkyl optionally substituted with one or moresubstituents selected from OH, 5-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S, and 5-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S.

In some embodiments of the formulae above, R₁₃ and R₁₅ together with thenitrogen atom to which they are attached form a 4- to 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, andthietanyl) and optionally substituted with one to three substituentsselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), and OH, or forma 5- to 8-membered bicyclic heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S and optionally substituted withone to three substituents selected from (C₁-C₄) alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), (C₁-C₄) alkoxy(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, ort-butoxy), and OH. In another embodiment, R₁₃ and R₁₅ together with thenitrogen atom to which they are attached form a 4- to 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS and optionally substituted with one to three substituents selectedfrom (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and OH. In another embodiment, R₁₃and R₁₅ together with the nitrogen atom to which they are attached forma 5- to 8-membered bicyclic heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S and optionally substituted withone to three substituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,and OH. In another embodiment, R₁₃ and R₁₅ together with the nitrogenatom to which they are attached form a 4- to 6-membered heterocyclylring comprising 1 to 3 heteroatoms selected from N, O, and S andoptionally substituted with one to three substituents selected from(C₁-C₄) alkyl, (C₁-C₄) alkoxy, and OH, or form a 7- to 8-memberedbicyclic heterocyclyl ring comprising 1 to 3 heteroatoms selected fromN, O, and S and optionally substituted with one to three substituentsselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and OH.

In some embodiments of the formulae above, R₂ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). Inanother embodiment, R₂ is H or (C₁-C₃) alkyl (e.g., methyl, ethyl,n-propyl, or i-propyl). In another embodiment, R₂ is H, methyl, orethyl. In another embodiment, R₂ is H or methyl. In a furtherembodiment, R₂ is H.

In some embodiments of the formulae above, when q is 0, R₁ and R₂together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclyl ring comprising 0 to 1 additional heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuryl, and dioxanyl) and optionally substituted with one totwo NR₆R₇. In another embodiment, when q is 0, R₁ and R₂ together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclyl ring comprising 0 to 1 additional heteroatoms selected fromN, O, and S and substituted with one to two NR₆R₇. In anotherembodiment, when q is 0, R₁ and R₂ together with the nitrogen atom towhich they are attached form a 5-membered heterocyclyl ring comprising 0to 1 additional heteroatoms selected from N, O, and S (e.g.,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl)and optionally substituted with one or more NR₆R₇. In anotherembodiment, when q is 0, R₁ and R₂ together with the nitrogen atom towhich they are attached form a 5-membered heterocyclyl ring comprising 0to 1 additional heteroatoms selected from N, O, and S and optionallysubstituted with one to two NR₆R₇. In another embodiment, when q is 0,R₁ and R₂ together with the nitrogen atom to which they are attachedform a 5-membered heterocyclyl ring comprising 0 to 1 additionalheteroatoms selected from N, O, and S and substituted with one to twoNR₆R₇. In another embodiment, when q is 0, R₁ and R₂ together with thenitrogen atom to which they are attached form a 6-membered heterocyclylring comprising 0 to 1 additional heteroatoms selected from N, O, and S(e.g., piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, anddioxanyl) and optionally substituted with one or more NR₆R₇. In anotherembodiment, when q is 0, R₁ and R₂ together with the nitrogen atom towhich they are attached form a 6-membered heterocyclyl ring comprising 0to 1 additional heteroatoms selected from N, O, and S and optionallysubstituted with one to two NR₆R₇. In another embodiment, when q is 0,R₁ and R₂ together with the nitrogen atom to which they are attachedform a 6-membered heterocyclyl ring comprising 0 to 1 additionalheteroatoms selected from N, O, and S and substituted with one to twoNR₆R₇.

In some embodiments of the formulae above, R₆ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). Inanother embodiment, R₆ is H or (C₁-C₃) alkyl (e.g., methyl, ethyl,n-propyl, or i-propyl). In another embodiment, R₆ is H, methyl, orethyl. In another embodiment, R₆ is H or methyl. In another embodiment,R₆ is H.

In some embodiments of the formulae above, R₇ is H or (C₁-C₄) alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl).In another embodiment, R₇ is (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) or C(═O)R₂₄. Inanother embodiment, R₇ is H, (C₁-C₃) alkyl (e.g., methyl, ethyl,n-propyl, or i-propyl), or C(═O)R₂₄. In another embodiment, R₇ is H,methyl, ethyl, or C(═O)R₂₄. In another embodiment, R₇ is methyl, ethyl,or C(═O)R₂₄. In another embodiment, R₇ is H or C(═O)R₂₄.

In some embodiments of the formulae above, R₂₄ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl)optionally substituted with one to three (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy). Inanother embodiment, R₂₄ is (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl) optionally substituted with oneto three 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuryl, and dioxanyl). In another embodiment, R₂₄ is (C₁-C₄)alkyl substituted with one to three substituents selected from (C₁-C₄)alkoxy and 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S. In another embodiment, R₂₄ is (C₁-C₂) alkyl(i.e., methyl or ethyl) optionally substituted with one to threesubstituents selected from (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) and 5- or6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, anddioxanyl). In another embodiment, R₂₄ is (C₁-C₂) alkyl optionallysubstituted with one to three substituents selected from (C₁-C₂) alkoxy(i.e., methoxy or ethoxy) and 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., piperidinyl, piperazinyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, and dioxanyl).

In some embodiments of the formulae above, R₃ is N(R₈)₂. In anotherembodiment, R₃ is NH₂, NHCH₃, N(CH₃)₂, or 4-methylpiperzinyl. In anotherembodiment, R₃ is H, NH₂, NHCH₃, N(CH₃)₂, or 4-methylpiperzinyl. Inanother embodiment, R₃ is H, NH₂, NHCH₃, or 4-methylpiperzinyl. In afurther embodiment, R₃ is H.

In some embodiments of the formulae above, at least one R₈ is (i) H,(ii) (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl), or (iii) 5- or 6-membered heterocyclyl comprising1 to 3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuryl, and dioxanyl) and optionallysubstituted with one or more (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In anotherembodiment, at least one R₈ is (i) H, (ii) (C₁-C₂) alkyl (i.e., methylor ethyl), or (iii) 5- or 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S and optionally substituted withone to three (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl). In another embodiment, at least one R₈ is(i) H, (ii) (C₁-C₂) alkyl, or (iii) 5-membered heterocyclyl comprising 1to 3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl) and optionallysubstituted with one to three (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In anotherembodiment, at least one R₈ is (i) H, (ii) (C₁-C₂) alkyl, or (iii)6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,O, and S (e.g., piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, and dioxanyl) and optionally substituted with one tothree (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl). In another embodiment, at least one R₈ is (i) H or(ii) (C₁-C₂) alkyl.

In some embodiments of the formulae above, two R₈ together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclyl ring comprising 0 to 1 additional heteroatoms selected fromN, O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, anddioxanyl) and optionally substituted with one to three (C₁-C₄) alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl).In another embodiment, two R₈ together with the nitrogen atom to whichthey are attached form a 5-membered heterocyclyl ring comprising 0 to 1additional heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl) and optionallysubstituted with one or more (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In anotherembodiment, two R₈ together with the nitrogen atom to which they areattached form a 6-membered heterocyclyl ring comprising 0 to 1additional heteroatoms selected from N, O, and S (e.g., piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl) andoptionally substituted with one or more (C₁-C₄) alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In anotherembodiment, two R₈ together with the nitrogen atom to which they areattached form a 5-membered heterocyclyl ring comprising 0 to 1additional heteroatoms selected from N, O, and S and optionallysubstituted with one to three (C₁-C₄) alkyl. In another embodiment, twoR₈ together with the nitrogen atom to which they are attached form a6-membered heterocyclyl ring comprising 0 to 1 additional heteroatomsselected from N, O, and S and optionally substituted with one to three(C₁-C₄) alkyl. In another embodiment, two R₈ together with the nitrogenatom to which they are attached form a 5-membered heterocyclyl ringcomprising 0 to 1 additional heteroatoms selected from N, O, and S andsubstituted with one to three (C₁-C₄) alkyl. In another embodiment, twoR₈ together with the nitrogen atom to which they are attached form a6-membered heterocyclyl ring comprising 0 to 1 additional heteroatomsselected from N, O, and S and substituted with one to three (C₁-C₄)alkyl.

In another embodiment, at least one R₈ is (i) H, (ii) (C₁-C₂) alkyl(i.e., methyl or ethyl), (iii) 6-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S (e.g., piperidinyl, piperazinyl,morpholinyl, tetrahydropyranyl, and dioxanyl) and optionally substitutedwith one to three (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl), or (iv) two R₈ together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclyl ring comprising 0 to 1 additional heteroatoms selected fromN, O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, anddioxanyl) and optionally substituted with one to three (C₁-C₄) alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl).In a further embodiment, at least one R₈ is (i) H, (ii) (C₁-C₂) alkyl(i.e., methyl or ethyl), or (iii) two R₈ together with the nitrogen atomto which they are attached form a 6-membered heterocyclyl ring (e.g.,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl)comprising 0 to 1 additional heteroatoms selected from N, O, and S andsubstituted with one to three (C₁-C₄) alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl).

In some embodiments of the formulae above, n is 0 or 1. In anotherembodiment, n is 1 or 2. In another embodiment, n is 0. In anotherembodiment, n is 1. In another embodiment, n is 2.

In some embodiments of the formulae above, p is 0 or 1. In anotherembodiment, p is 1 or 2. In another embodiment, p is 0. In anotherembodiment, p is 1. In another embodiment, p is 2.

In some embodiments of the formulae above, r is 0, 1 or 2. In anotherembodiment, r is 1, 2, or 3. In another embodiment, r is 0 or 1. Inanother embodiment, r is 1 or 2. In another embodiment, r is 2 or 3. Inanother embodiment, r is 0. In another embodiment, r is 1. In anotherembodiment, r is 2. In another embodiment, r is 3.

In some embodiments of the formulae above, q is 0, 1 or 2. In anotherembodiment, q is 1, 2, or 3. In another embodiment, q is 0 or 1. Inanother embodiment, q is 1 or 2. In another embodiment, q is 2 or 3. Inanother embodiment, q is 0. In another embodiment, q is 1. In anotherembodiment, q is 2. In another embodiment, q is 3.

In some embodiments of the formulae above, x is 0, 1 or 2. In anotherembodiment, x is 1, 2, or 3. In another embodiment, x is 0 or 1. Inanother embodiment, x is 1 or 2. In another embodiment, x is 2 or 3. Inanother embodiment, x is 0. In another embodiment, x is 1. In anotherembodiment, x is 2. In another embodiment, x is 3.

In some embodiments of the formulae above, when R₄ is NR₉S(O)_(p)R₁₀,O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁, (CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅,(CH₂)_(n)NHC(═O)NHR₂₅, C(═O)R₂₅, or heterocyclyl comprising one or two4- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and Sand optionally substituted with one or more substituents selected from(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, C(═O)(C₁-C₄) alkyl, and halogen, A isoptionally substituted with one additional R₄. In some embodiments ofthe formulae above, when R₄ is NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁,NH(CH₂)_(n)R₁₁, (CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅,(CH₂)_(n)NHC(═O)NHR₂₅, or C(═O)R₂₅, A is optionally substituted with oneadditional R₄. In some embodiments of the formulae above, when R₄ is(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅, orC(═O)R₂₅, A is optionally substituted with one additional R₄. In someembodiments of the formulae above, when R₄ is (CH₂)_(n)C(═O)NHR₂₅ or(CH₂)_(n)NHC(═O)R₂₅, A is optionally substituted with one additional R₄.In some embodiments of the formulae above, when R₄ is O(CH₂)_(n)R₁₁ orNH(CH₂)_(n)R₁₁, A is optionally substituted with one additional R₄.

In some embodiments of the formulae above, when R₄ is(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅, or NR₉S(O)_(p)R₁₀, A isoptionally substituted with one additional R₄.

In some embodiments of the formulae above, A is substituted with one totwo R₄ and R₄ is (C₁-C₄) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, or t-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), (C₁-C₄)haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl,etc.), (C₁-C₄) haloalkoxy (e.g., OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃,OCCl₃, OCHCl₂, OCH₂Cl, etc.), halogen (e.g., F, Cl, Br, or I),NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁, (CH₂)_(n)C(═O)NHR₂₅,(CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅, or C(═O)R₂₅. In anotherembodiment, A is substituted with one or more R₄ and R₄ is (C₁-C₄) alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, or t-butoxy), (C₁-C₄) haloalkyl (e.g., CF₃, CHF₂, CH₂F,CH₂CF₃, CF₂CF₃, CCl₃, CHCl₂, CH₂Cl, etc.), (C₁-C₄) haloalkoxy (e.g.,OCF₃, OCHF₂, OCH₂F, OCH₂CF₃, OCF₂CF₃, OCCl₃, OCHCl₂, OCH₂Cl, etc.),halogen (e.g., F, Cl, Br, or I), O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁,(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅, orC(═O)R₂₅.

In some embodiments of the formulae above, the compounds of Formula (I)is not(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.

In some embodiments of the formulae above, A is phenyl, thiophenyl, orpyridinyl optionally substituted with one or more R₄.

In some embodiments of the formulae above, A is phenyl, thiophenyl, orpyridinyl substituted with one to two R₄.

In some embodiments of the formulae above, A is phenyl substituted withone to two R₄.

In some embodiments of the formulae above, R₃ is H, NH₂, NHCH₃, or4-methylpiperazine.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, or t-butoxy), halogen (e.g., F, Cl, Br, or I),NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁, C(═O)NHR₂₅, NHC(═O)R₂₅,NHC(═O)NHR₂₅, (CH₂)C(═O)NHR₂₅, (CH₂)NHC(═O)R₂₅, (CH₂)NHC(═O)NHR₂₅, orC(═O)R₂₅.

In some embodiments of the formulae above, at least one R₄ is (C₁-C₄)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ort-butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, or t-butoxy), halogen (e.g., F, Cl, Br, or I), orO(CH₂)_(n)R₁₁, C(═O)NHR₂₅, NHC(═O)R₂₅, NHC(═O)NHR₂₅, (CH₂)C(═O)NHR₂₅,(CH₂)NHC(═O)R₂₅, (CH₂)NHC(═O)NHR₂₅, or C(═O)R₂₅.

In some embodiments of the formulae above, R₁₁ is (C₆-C₁₀) aryl or 5- or6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O,and S, wherein the aryl and heteroaryl are optionally substituted withone to three R₁₇.

In some embodiments of the formulae above, R₁₁ is phenyl or pyridinyl,and is optionally substituted with one to three R₁₇.

In some embodiments of the formulae above, R₁ is (C₄-C₆) cycloalkyl(e.g., cyclobutyl, cyclopentyl, cyclohexyl) substituted with one tothree R₅.

In some embodiments of the formulae above, R₁ is cyclohexyl substitutedwith one to three R₅.

In some embodiments of the formulae above, R₁ is 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and Soptionally substituted with one to three R₅.

In some embodiments of the formulae above, R₁ is piperidinyl,tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyloptionally substituted with one to three R₅.

In some embodiments of the formulae above, R₁ is tetrahydropyranyloptionally substituted with one to three R₅.

In some embodiments of the formulae above, each R₄ is independently(C₁-C₄) alkyl, (C₁-C₄) alkoxy optionally substituted with one or more(C₁-C₄) alkoxy, halogen, NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁1,C(═O)NHR₂₅, NHC(═O)R₂₅, NHC(═O)NHR₂₅, (CH₂)C(═O)NHR₂₅, (CH₂)NHC(═O)R₂₅,(CH₂)NHC(═O)NHR₂₅, C(═O)R₂₅, or 5- or 6-membered heterocyclyl comprising1 to 3 heteroatoms selected from N, O, and S and optionally substitutedwith one or more (C₁-C₄) alkyl.

In some embodiments of the formulae above, each R₄ is independently(C₁-C₄) alkyl, (C₁-C₄) alkoxy, halogen, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁,C(═O)NHR₂₅, NHC(═O)R₂₅, NHC(═O)NHR₂₅, (CH₂)C(═O)NHR₂₅, (CH₂)NHC(═O)R₂₅,(CH₂)NHC(═O)NHR₂₅, C(═O)R₂₅, or 5- or 6-membered heterocyclyl comprising1 to 3 heteroatoms selected from N, O, and S and optionally substitutedwith one or more (C₁-C₄) alkyl.

In some embodiments of the formulae above, R₁ is (C₄-C₇) cycloalkylsubstituted with one to three R₅.

In some embodiments of the formulae above, R₁ is 4- to 7-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and Soptionally substituted with one to three R₅.

In some embodiments of the formulae above, R₅ is C(═O)R₁₆ or S(O)_(p)R₁₆and R₁₆ is (C₂-C₄) alkenyl or (C₂-C₄) alkynyl, wherein the alkenyl andalkynyl are optionally substituted with one or more CN.

In some embodiments of the formulae above, two R₅ together with theatoms to which they are attached form a bridged 3- to 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is (C₆-C₁₀) aryl optionally substituted with one to two R₄. Inanother embodiment, R₂ is H, R₃ is H, and A is (C₆-C₁₀) aryl optionallysubstituted with one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4-to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected fromN, O, and S, wherein the cycloalkyl and heterocyclyl are optionallysubstituted with one to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is (C₆-C₁₀) aryl substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is (C₆-C₁₀) aryl substituted withone to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is phenyl optionally substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is phenyl optionally substitutedwith one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is phenyl substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is phenyl substituted with one totwo R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S and optionally substituted with one to two R₄.In another embodiment, R₂ is H, R₃ is H, and A is 5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S andoptionally substituted with one to two R₄, and R₁ is (C₃-C₇) cycloalkyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl)or 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selectedfrom N, O, and S, wherein the cycloalkyl and heterocyclyl are optionallysubstituted with one to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S and substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S and substitutedwith one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is 5-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom N, O, and S and optionally substituted with one to two R₄. Inanother embodiment, R₂ is H, R₃ is H, and A is 5-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S and optionallysubstituted with one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4-to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected fromN, O, and S, wherein the cycloalkyl and heterocyclyl are optionallysubstituted with one to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is 5-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom N, O, and S and substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is 5-membered heteroaryl comprising1 to 3 heteroatoms selected from N, O, and S and substituted with one totwo R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is 6-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom N, O, and S and optionally substituted with one to two R₄. Inanother embodiment, R₂ is H, R₃ is H, and A is 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S and optionallysubstituted with one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4-to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected fromN, O, and S, wherein the cycloalkyl and heterocyclyl are optionallysubstituted with one to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is 6-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom N, O, and S and substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S and substitutedwith one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is pyridinyl optionally substituted with one to two R₄. Inanother embodiment, R₂ is H, R₃ is H, and A is pyridinyl optionallysubstituted with one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4-to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected fromN, O, and S, wherein the cycloalkyl and heterocyclyl are optionallysubstituted with one to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is pyridinyl substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is pyridinyl substituted with one totwo R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is thiophenyl optionally substituted with one to two R₄. Inanother embodiment, R₂ is H, R₃ is H, and A is thiophenyl optionallysubstituted with one to two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4-to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected fromN, O, and S, wherein the cycloalkyl and heterocyclyl are optionallysubstituted with one to three R₅.

In some embodiments of the formulae above, R₂ is H. In anotherembodiment, R₂ is H and R₃ is H. In another embodiment, R₂ is H, R₃ isH, and A is thiophenyl substituted with one to two R₄. In anotherembodiment, R₂ is H, R₃ is H, and A is thiophenyl substituted with oneto two R₄, and R₁ is (C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the cycloalkyl and heterocyclyl are optionally substituted withone to three R₅.

In some embodiments of the formulae above, R₁ is a heterocycloalkylselected from:

wherein W is O, S, NH, or N(C₁-C₆)alkyl.

Non-limiting illustrative compounds of the application include:

Cmpd No. Structure Chemical name I-1

(2-chlorophenyl)(4-((trans-4- hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-2

tert-butyl (cis-4-((5-(2-chlorobenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate I-3

tert-butyl ((1S,3R)-3-((5-(2- chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclopentyl)carbamate I-4

(4-((3-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone I-5

(4-((trans-4-aminocyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone I-6

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone I-7

(4-(((1R,3S)-3- aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2- chlorophenyl)methanone I-8

N-(trans-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(1- methylpiperidin-4-yl)acetamide I-9

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(1- methylpiperidin-4-yl)acetamide I-10

N-((1S,3R)-3-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclopentyl)-2-(1- methylpiperidin-4-yl)acetamide I-11

N-(3-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(1- methylpiperidin-4-yl)acetamide I-12

tert-butyl (cis-4-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate I-13

(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(o-tolyl)methanone I-14

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone I-15

N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(4- methylpiperazin-1-yl)acetamide I-16

(4-((1-methylpiperidin-4-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone I-17

tert-butyl 4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate I-18

(4-((cis-4- (dimethylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-19

methyl trans-4-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexane-1-carboxylate I-20

(4-(((3R,6S)-6-(2-hydroxypropan-2- yl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-21

(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-22

(4-((cis-4-hydroxycyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone I-23

((2S,5R)-5-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)(4- methylpiperazin-1-yl)methanoneI-24

(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(o-tolyl)methanone I-25

4-(tert-butyl)-N-(cis-4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)benzamide I-26

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone I-27

(S)-(4-(((1,4-dioxan-2- yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone I-28

2-(4-(4-(tert-butyl)benzoyl)piperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-29

2-(4-benzoylpiperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-30

N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)benzamide I-31

(2-chlorophenyl)(4-((cis-4- hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-32

(2-chlorophenyl)(4-((trans-4- hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-33

N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-34

(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N- ((tetrahydro-2H-pyran-4-yl)methyl)tetrahydro-2H-pyran-2- carboxamide I-35

tert-butyl ((3R,6S)-6-(((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)tetrahydro-2H-pyran- 3-yl)carbamate I-36

4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexan-1- one I-37

(trans-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(4- methylpiperazin-1-yl)methanone I-38

(2-chlorophenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-39

(4-((cis-4- (benzylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-40

2-(4-benzylpiperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-41

(4-((cis-4- (hydroxymethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-42

(2S,5R)-N-(((S)-1,4-dioxan-2- yl)methyl)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)tetrahydro-2H-pyran-2- carboxamideI-43

(2-chlorophenyl)(4-((cis-4- (methylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-44

(2-chlorophenyl)(4-((cis-4- (dimethylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-45

N-(trans-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-46

(4-((((2S,5R)-5-aminotetrahydro-2H- pyran-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-47

N-(((2S,5R)-5-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2- yl)methyl-2-(4-methylpiperazin-1-yl)acetamide I-48

(2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N- ((tetrahydro-2H-pyran-4-yl)methyl)tetrahydro-2H-pyran-2- carboxamide I-49

(2-chlorophenyl)(4-(((3R,6S)-6-(2- hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-50

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-N- methylacetamide I-51

1-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)pyrrolidin-2-one I-52

1-(4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one I-53

2-methoxy-1-(4-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one I-54

3-methoxy-1-(4-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)propan-1-one I-55

2-(dimethylamino)-1-(4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)ethan-1-one I-56

(4-((1-(2-methoxyethyl)piperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(o-tolyl)methanone I-57

(4-(((4- aminocyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-58

(4-((4- (aminomethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-59

(4-((4-((4-(tert- butyl)benzyl)amino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-60

(4-((4-((3,5- dichlorobenzyl)amino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-61

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-N-methyl-2- (tetrahydro-2H-pyran-4-yl)acetamideI-62

cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexane-1-carboxylic acid I-63

cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexane-1-carboxamide I-64

cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1- carboxamide I-65

cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)cyclohexane- 1-carboxamide I-66

cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-((tetrahydro-2H-pyran-4- yl)methyl)cyclohexane-1-carboxamide I-67

cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(2-(pyridin-3-yl)ethyl)cyclohexane-1- carboxamide I-68

cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methylcyclohexane-1-carboxamide I-69

(2-chlorophenyl)(4-((cis-4-(pyrrolidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-70

(4-((cis-4-(azetidin-1- yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2- chlorophenyl)methanone I-71

(4-((trans-4-(azetidin-1- yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2- chlorophenyl)methanone I-72

N-(4-(tert-butyl)benzyl)-2-methyl-2- ((cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)cyclohexyl) amino)propanamideI-73

N-benzyl-2-methyl-2-((cis-4-(((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)cyclohexyl) amino)propanamide I-74

N-(cis-4-(((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)cyclohexyl)benzamide I-75

N-((cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methyl)benzamide I-76

(4-((1S,2S)-2- (hydroxymethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-77

(4-((1- (hydroxymethyl)cyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-78

(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(morpholino) methanone I-79

(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)((2S,6R)-2,6- dimethylmorpholino)methanone I-80

(4-((cis-4-((1R,5S)-8-oxa-3- azabicyclo[3.2.1]octane-3-carbonyl)cyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone I-81

(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(3- hydroxyazetidin-1-yl)methanone I-82

(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(4- methylpiperazin-1-yl)methanone I-83

(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)((3S,5R)-3,5- dimethylpiperazin-1-yl)methanone I-84

N-(trans-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-85

(S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- hydroxypropanamide I-86

(R)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- hydroxypropanamide I-87

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- methoxyacetamide I-88

(2-chlorophenyl)(4-((cis-4-(3- hydroxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-89

(2-chlorophenyl)(4-((trans-4-(3- hydroxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-90

methyl (2S,5R)-5-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-carboxylate I-91

(2S,5R)-5-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2- carboxamide I-92

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propionamide I-93

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)isobutyramide I-94

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl) cyclopropanecarboxamide I-95

4-methyl-N-(cis-4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclohexyl)benzamide I-96

3-methyl-N-(cis-4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclohexyl)benzamide I-97

2-methyl-N-(cis-4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclohexyl)benzamide I-98

(S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- methoxypropanamide I-99

(R)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- methoxypropanamide I-100

(S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)tetrahydrofuran-2- carboxamide I-101

(R)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)tetrahydrofuran-2- carboxamide I-102

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1- hydroxycyclopropane-1-carboxamide I-103

(2-chlorophenyl)(4-((cis-4-hydroxy-4- methylcyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-104

(2-chlorophenyl)(4-((trans-4-hydroxy-4- methylcyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-105

trans-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexane-1-carboxamide I-106

(S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxy-N- methylpropanamide I-107

(2-chlorophenyl)(4-((trans-4-hydroxy-4-(methoxymethyl)cyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-108

(2-chlorophenyl)(4-((cis-4-hydroxy-4- (methoxymethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-109

(2-chlorophenyl)(4-((cis-4-(3- methoxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-110

(2-chlorophenyl)(4-((trans-4-(3- methoxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-111

(2-chlorophenyl)(4-((cis-4-(3-hydroxy- 3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-112

(2-chlorophenyl)(4-((trans-4-(3- hydroxy-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-113

(4-((cis-4-(3-amino-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-chlorophenyl)methanone I-114

(4-((trans-4-(3-amino-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-chlorophenyl)methanone I-115

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxy-2- methylpropanamide I-116

N-((S)-1-((2S,5R)-5-((5-(2- chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide I-117

N-((S)-1-((2S,5R)-5-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide I-118

N-(((2S,5R)-5-((5-(2-chlorobenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2- yl)methyl)acetamide I-119

N-(((2S,5R)-5-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2- yl)methyl)acetamide I-120

N-(3-(4-((cis-4- aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)methanesulfonamide I-121

N-(3-(4-((cis-4- aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzenesulfonamide I-122

N-((S)-1-((2S,5R)-5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide I-124

(2-chloro-4-phenoxyphenyl)(4- (((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-125

(2-chloro-4-phenoxyphenyl)(4- (((3R,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-126

(2-chloro-4-phenoxyphenyl)(4- (((3S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-127

N-(((2S,5R)-5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)acetamide I-128

2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(3-methylthiophene-2-carbonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-129

(4-((4-methylcyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(3-methylthiophen-2-yl)methanone I-130

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone I-131

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(3-phenoxyphenyl)methanone I-132

2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(2-methylthiophene-3-carbonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-133

tert-butyl (cis-4-((5-(3- methoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclohexyl)carbamate I-134

tert-butyl (cis-4-((5-(5-methoxy-2- methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)carbamate I-135

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(3-methoxyphenyl)methanone I-136

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(5-methoxy-2-methylphenyl)methanone I-137

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro- 5-methoxyphenyl)methanone I-138

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-fluoro- 3-methoxyphenyl)methanone I-139

N-(cis-4-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-140

N-(cis-4-((5-(3-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-141

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro- 4-phenoxyphenyl)methanone I-142

(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-phenoxyphenyl)methanoneI-143

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(2- methoxyethoxy)phenyl)methanone I-144

rac-(4-((cis-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-phenoxyphenyl)methanoneI-145

rac-(4-((trans-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-phenoxyphenyl)methanoneI-146

(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-phenoxyphenyl)methanoneI-147

(4-(((3R,6S)-6-(2-hydroxypropan-2- yl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-148

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(3- fluorophenoxy)phenyl)methanone I-149

(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(pyridin-3-yloxy)phenyl)methanone I-150

(2-chloro-4-phenoxyphenyl)(4- (((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-151

N-(cis-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-152

N-(cis-4-((5-(4-(4- fluorophenoxy)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-153

N-(cis-4-((5-(4-(3- (trifluoromethyl)phenoxy)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-154

(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(4-(benzyloxy)phenyl)methanone I-155

rac-(4-phenoxyphenyl)(4-((tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-156

(4-phenoxyphenyl)(4-((tetrahydro-2H- pyran-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-157

(2S,5R)-5-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2- carboxamide I-158

(4-((trans-4-(1,3,4-oxadiazol-2- yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-159

(4-((trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone I-160

(4-(((3R,6S)-6-((S)-1- hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-phenoxyphenyl)methanoneI-161

N-(cis-4-((5-(4-(4- chlorophenoxy)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-162

N-(cis-4-((5-(4-(p-tolyloxy)benzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide I-163

N-(cis-4-((5-(4-(cyclohex-2-en-1- yloxy)benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-164

N-(cis-4-((5-(2-chloro-6- phenoxynicotinoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-165

(4-((trans-4- (hydroxymethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-166

(4-(((3R,6S)-6-((S)-1- aminoethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(2-chloro-4-phenoxyphenyl)methanone I-167

(2-chloro-4-phenoxyphenyl)(4- (((3R,6S)-6-((S)-1-(dimethylamino)ethyl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-168

(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-169

(2-chloro-4-phenoxyphenyl)(4-((trans- 4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-170

2-(dimethylamino)-N-(cis-4-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-171

(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(pyridin-2-yloxy)phenyl)methanone I-172

(4-((6-chloropyridin-2- yl)oxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-173

(R)-(2-chloro-4-phenoxyphenyl)(4- ((tetrahydrofuran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-174

(S)-(2-chloro-4-phenoxyphenyl)(4- ((tetrahydrofuran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-175

(2S,5R)-N-((2R,3R)-1,3- dihydroxybutan-2-yl)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide I-176

(2S,5R)-N-((R)-2,3-dihydroxypropyl)-5- ((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)tetrahydro-2H-pyran-2- carboxamideI-177

(2-chloro-4-phenoxyphenyl)(4-((trans- 4-((dimethylamino)methyl)-4-hydroxycyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanoneI-178

(2-chloro-4-phenoxyphenyl)(4-((cis-4- ((dimethylamino)methyl)-4-hydroxycyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanoneI-179

rac-(2-chloro-4-phenoxyphenyl)(4- (((1S,3S,4R)-3,4-dihydroxycyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanoneI-180

rac-(2-chloro-4-phenoxyphenyl)(4- (((1S,3R,4S)-3,4-dihydroxycyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanoneI-181

N-(cis-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- (dimethylamino)acetamide I-182

(2-chloro-4-(3- fluorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-183

(2-chloro-4-(3- chlorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-184

tert-butyl ((1S,3S)-3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclopentyl)carbamate I-185

tert-butyl (trans-3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl)carbamate I-186

tert-butyl (cis-3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclobutyl)carbamate I-187

(4-((trans-3- (hydroxymethyl)cyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-188

(2-chloro-4-phenoxyphenyl)(4- (((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-189

(4-(((1R,3R)-3- aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-190

(4-((cis-3-aminocyclobutyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone I-191

(4-((trans-3 -aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-192

N-((1R,3R)-3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclopentyl)acetamide I-193

(S)-N-(cis-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- hydroxypropanamide I-194

N-(cis-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2- hydroxy-2-methylpropanamide I-195

N-((R)-1-((2S,5R)-5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide I-196

N-(cis-3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)acetamide I-197

(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(2-methyl-4-phenoxyphenyl)methanone I-198

N-((S)-1-((2S,5R)-5-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide I-199

N-(trans-3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)acetamide I-200

(2-chloro-4-phenoxyphenyl)(4-((cis-4- hydroxy-4-methylcyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-201

(2-chloro-4-phenoxyphenyl)(4-((trans-4-hydroxy-4-methylcyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-202

(S)-2-hydroxy-N-(cis-4-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)propanamide I-203

2-hydroxy-2-methyl-N-(cis-4-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)propanamide I-204

N-((S)-1-((2S,5R)-5-((5-(2-methyl-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide I-205

N-(((2S,5R)-5-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2- yl)methyl)acetamide I-206

(R)-2-hydroxy-N-(cis-4-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)propanamide I-207

(2-chloro-4-phenoxyphenyl)(4-((trans-3-(hydroxymethyl)cyclobutyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-208

(S)-N-((S)-1-((2S,5R)-5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)-2-hydroxypropanamide I-209

(S)-2-hydroxy-N-((S)-1-((2S,5R)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)propanamide I-210

(S)-N-(((2S,5R)-5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)-2-hydroxypropanamide I-211

(S)-2-hydroxy-N-(((2S,5R)-5-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)propanamideI-212

rac-N-(cis-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-6- hydroxyheptanamide I-213

(R)-N-((S)-1-((2S,5R)-5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)-2-hydroxypropanamide I-214

rac-N-(cis-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-7- hydroxyoctanamide I-215

(R)-2-hydroxy-N-((S)-1-((2S,5R)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)propanamide I-216

(R)-N-(((2S,5R)-5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)-2-hydroxypropanamide I-217

(R)-2-hydroxy-N-(((2S,5R)-5-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)propanamideI-218

(4-((cis-4-aminocyclohexyl)amino)-2- ((1-methylpiperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-219

(2-amino-4-(cis-4- aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-220

(4-((cis-4-aminocyclohexyl)amino)-2- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone I-221

(4-((cis-4-aminocyclohexyl)amino)-2- (4-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-222

N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(4- methylpiperazin-1-yl)acetamide I-223

rac-(4-(3-aminopyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone I-224

rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide I-225

rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrrolidin-3-yl)-3-methoxypropanamide I-226

rac-tert-butyl 3-((5-benzoyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1-carboxylate I-227

rac-phenyl(4-(pyrrolidin-3-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-228

rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan- 1-one I-229

rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)-3-methoxypropan-1-one I-230

1-(3-((5-benzoyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one

In another embodiment, non-limiting examples of compounds of theinvention include:

Cmpd No. Structure Chemical name I-231

4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-232

4-(4-((6-(hydroxymethyl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N- phenylbenzamide I-233

4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-234

4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-235

4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-236

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-237

3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-238

3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-239

3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-240

3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-241

4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-242

4-(4-((6-(hydroxymethyl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4- yl)benzamide I-243

4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-244

4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-245

4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-246

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-247

3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-248

3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-249

3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-250

3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide I-251

4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-252

4-(4-((6-(hydroxymethyl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3- yl)benzamide I-253

4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-254

4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-255

4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-256

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-257

3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-258

3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-259

3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-260

3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide I-261

4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-262

4-(4-((6-(hydroxymethyl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2- yl)benzamide I-263

4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-264

4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-265

4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-266

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-267

3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-268

3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-269

3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-270

3-chloro-4-(4-((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-2-yl)benzamide I-271

N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-272

N-(4-(4-((6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl)benzamide I-273

N-(4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-274

N-(4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-275

N-(4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-276

N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-277

N-(3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-278

N-(3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-279

N-(3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-280

N-(3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-281

N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-282

N-(4-(4-((6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl)isonicotinamide I-283

N-(4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-284

N-(4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-285

N-(4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-286

N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-287

N-(3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-288

N-(3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-289

N-(3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-290

N-(3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isonicotinamideI-291

N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-292

N-(4-(4-((6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl)nicotinamide I-293

N-(4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-294

N-(4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-295

N-(4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-296

N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-297

N-(3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-298

N-(3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-299

N-(3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-300

N-(3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)nicotinamideI-301

N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-302

N-(4-(4-((6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl)picolinamide I-303

N-(4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-304

N-(4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-305

N-(4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-306

N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-307

N-(3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-308

N-(3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-309

N-(3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-310

N-(3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-311

(2-chloro-4-morpholinophenyl)(4- (((3S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-311i

(2-chloro-4-morpholinophenyl)(4- (((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-312

(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-morpholinophenyl)methanoneI-313

(2-chloro-4-(4-methylpiperazin-1- yl)phenyl)(4-(((3S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-314

(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(4-methylpiperazin-1-yl)phenyl)methanone I-315

(4-(4-butylpiperazin-1-yl)-2- chlorophenyl)(4-(((3S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-316

(4-(4-butylpiperazin-1-yl)phenyl)(4-(((3S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-317

(2-chloro-4-(2- methoxyethoxy)phenyl)(4-(((3S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-317i

2-chloro-4-(2- methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-318

(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(2-methoxyethoxy)phenyl)methanone I-318i

(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(2-methoxyethoxy)phenyl)methanone I-319

6-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenoxy)-N-methylpicolinamide I-320

6-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenoxy)-N-methylpicolinamide I-321

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1- one I-321r

(racemic)-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)prop-2-en-1-one I-322

(2-chloro-4-phenoxyphenyl)(4-((1- (vinylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-322r

(racemic)-(2-chloro-4- phenoxyphenyl)(4-((1-(vinylsulfonyl)piperidin-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-323

(E)-2-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)but-2-enenitrile I-324

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one I-324r

(racemic)-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)but-2-yn-1-one I-325

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1-one I-325r

(racemic)-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1-one I-326

(2-chloro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)pyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-326r

(racemic)-(2-chloro-4- phenoxyphenyl)(4-(((1-(vinylsulfonyl)pyrrolidin-2- yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-327

(E)-2-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1- carbonyl)but-2-enenitrileI-328

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)but-2- yn-1-one I-328r

(racemic)-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)but-2- yn-1-one I-329

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-330

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-331

(2-chloro-4-phenoxyphenyl)(4-((1- (hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-332

(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)quinuclidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-333

(2-chloro-4-phenoxyphenyl)(4-((7- (hydroxymethyl)oxepan-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-334

(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)tetrahydro-2H-thiopyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-335

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)tetrahydrofuran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-336

(2-chloro-4-phenoxyphenyl)(4-((2- (hydroxymethyl)oxetan-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-337

(2-chloro-4-phenoxyphenyl)(4-((1- ethyl-6-(hydroxymethyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-338

(2-chloro-4-phenoxyphenyl)(4-((1- ethyl-6-(1-hydroxyethyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-339

(2-chloro-4-phenoxyphenyl)(4-((1- ethyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-340

(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)-1-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-341

(2-chloro-4-phenoxyphenyl)(4-((6-(1- hydroxyethyl)-1-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-342

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)-1-methylpyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-342e

(2-chloro-4-phenoxyphenyl)(4- (((3R,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanoneI-343

(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-343r

(racemic)-(2-chloro-4- phenoxyphenyl)(4-((6-(hydroxymethyl)piperidin-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-344

(2-chloro-4-phenoxyphenyl)(4-((6-(1-hydroxyethyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-345

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-345e

(2-chloro-4-phenoxyphenyl)(4- (((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-346

(2-chloro-4-phenoxyphenyl)(4-((6-(1-hydroxyethyl)tetrahydro-2H-thiopyran- 3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-347

(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)tetrahydro-2H-thiopyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-348

(2-chloro-4-phenoxyphenyl)(4-((6-(1- hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-349

(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-350

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)tetrahydrofuran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-351

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)tetrahydrothiophen-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-352

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)tetrahydrofuran-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-353

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)tetrahydrothiophen-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-354

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)pyrrolidin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-355

(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)-1-methylpyrrolidin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-356

(2-chloro-4-phenoxyphenyl)(7-ethyl-4- ((5-(hydroxymethyl)pyrrolidin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-357

(2-chloro-4-phenoxyphenyl)(4-(((6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-358

(2-chloro-4-phenoxyphenyl)(4-(((6- (hydroxymethyl)tetrahydro-2H-thiopyran-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanoneI-359

(2-chloro-4-phenoxyphenyl)(4-(((6- (hydroxymethyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-359e

racemic-cis-(2-chloro-4- phenoxyphenyl)(4-(((6-(hydroxymethyl)piperidin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanoneI-360

(2-chloro-4-phenoxyphenyl)(4-(((6- (hydroxymethyl)-1-methylpiperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-360e

racemic-cis-(2-chloro-4- phenoxyphenyl)(4-(((6-(hydroxymethyl)-1-methylpiperidin-2- yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-361

(2-chloro-4-phenoxyphenyl)(4-(((1- ethyl-6-(hydroxymethyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-362

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)tetrahydrofuran-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-362e

(2-chloro-4-phenoxyphenyl)(4- ((((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2- yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-363

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)tetrahydrofuran-3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-364

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)tetrahydrothiophen-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-365

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)tetrahydrothiophen-3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-366

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)pyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-367

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)-1-methylpyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-368

(2-chloro-4-phenoxyphenyl)(4-(((1- ethyl-5-(hydroxymethyl)pyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-369

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-369e

(2-chloro-4-phenoxyphenyl)(4- ((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-370

(2-chloro-4-phenoxyphenyl)(4-(((5- (hydroxymethyl)-1-methylpyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-370e

(2-chloro-4-phenoxyphenyl)(4- ((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)methyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-371

(2-chloro-4-phenoxyphenyl)(4-(((1- ethyl-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-372

1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1- one I-373

(4-phenoxyphenyl)(4-((1- (vinylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-374

(E)-2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carbonyl)but-2- enenitrile I-375

1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one I-376

1-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1-one I-377

(4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)pyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-378

(E)-2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1- carbonyl)but-2-enenitrile I-379

1-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)but-2- yn-1-one I-380

1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1- one I-381

(2-fluoro-4-phenoxyphenyl)(4-((1- (vinylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-382

(E)-2-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)but-2-enenitrile I-383

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one I-384

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1-one I-385

(2-fluoro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)pyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-386

(E)-2-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1- carbonyl)but-2-enenitrileI-387

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)but-2- yn-1-one I-388

1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one I-389

(4-phenoxyphenyl)(4-((1- (vinylsulfonyl)azepan-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-390

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one I-391

(2-chloro-4-phenoxyphenyl)(4-((1- (vinylsulfonyl)azepan-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-392

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one I-393

(2-fluoro-4-phenoxyphenyl)(4-((1- (vinylsulfonyl)azepan-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-394

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)but-2-yn-1-one I-395

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)but-2-yn-1-one I-396

1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)but-2-yn-1-one I-397

(E)-2-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1- carbonyl)but-2-enenitrile I-398

(E)-2-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1- carbonyl)but-2-enenitrile I-399

(E)-2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1-carbonyl)but-2- enenitrile I-400

1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1- one I-401

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1- one I-402

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1- one I-403

(2-chloro-4-phenoxyphenyl)(4-((1- (vinylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-404

(2-fluoro-4-phenoxyphenyl)(4-((1- (vinylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-405

(4-phenoxyphenyl)(4-((1- (vinylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-406

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one I-407

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one I-408

1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one I-409

(E)-2-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)but-2-enenitrile I-410

(E)-2-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)but-2-enenitrile I-411

(E)-2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1-carbonyl)but-2- enenitrile I-412

oxiran-2-yl(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)methanone I-413

(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)(oxiran-2- yl)methanone I-414

(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)(oxiran-2- yl)methanone I-415

(3-methyloxiran-2-yl)(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)methanone I-416

(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)(3- methyloxiran-2-yl)methanone I-417

(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)(3- methyloxiran-2-yl)methanone I-418

methyl 3-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)oxirane-2-carboxylate I-419

methyl 3-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)oxirane-2-carboxylateI-420

methyl 3-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)oxirane-2-carboxylateI-421

(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(oxiran-2- yl)methanone I-422

(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(oxiran-2- yl)methanone I-423

oxiran-2-yl(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methanone I-424

(3-methyloxiran-2-yl)(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)methanone I-425

(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(3- methyloxiran-2-yl)methanone I-426

(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(3- methyloxiran-2-yl)methanone I-427

methyl 3-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)oxirane-2-carboxylateI-428

methyl 3-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)oxirane-2-carboxylateI-429

methyl 3-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carbonyl)oxirane- 2-carboxylate I-430

oxiran-2-yl(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)methanone I-431

(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)(oxiran-2- yl)methanone I-432

(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)(oxiran-2- yl)methanone I-433

(3-methyloxiran-2-yl)(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)methanone I-434

(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)(3-methyloxiran- 2-yl)methanone I-435

(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)(3-methyloxiran- 2-yl)methanone I-436

methyl 3-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1-carbonyl)oxirane-2- carboxylate I-437

methyl 3-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1- carbonyl)oxirane-2-carboxylate I-438

methyl 3-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1- carbonyl)oxirane-2-carboxylate I-439

(E)-5-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)pent-3-en-2-one I-440

(E)-5-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)pent-3-en-2-one I-441

(E)-5-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)pent-3-en-2-one I-442

(E)-5-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)pent-3-en-2-one I-443

(E)-5-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)pent-3-en-2-one I-444

(E)-5-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)pent-3-en-2-one I-445

(E)-5-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)pent-3-en-2-one I-446

(E)-5-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)pent-3-en-2-one I-447

(E)-5-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)pent-3-en-2- one I-448

2-chloro-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)ethan-1-one I-449

2-chloro-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-450

2-chloro-1-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-451

2-bromo-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)ethan-1-one I-452

2-bromo-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-453

2-bromo-1-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-454

2-iodo-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)ethan-1-one I-455

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-iodoethan- 1-one I-456

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-iodoethan- 1-one I-457

2-phenoxy-1-(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-458

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2- phenoxyethan-1-one I-459

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2- phenoxyethan-1-one I-460

2-oxo-2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)ethyl methanesulfonate I-461

2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-oxoethyl methanesulfonate I-462

2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-oxoethyl methanesulfonate I-463

2-chloro-1-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-464

2-chloro-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-465

2-chloro-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)ethan-1-one I-466

2-bromo-1-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-467

2-bromo-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-468

2-bromo-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)ethan-1-one I-469

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)-2-iodoethan-1- one I-470

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)-2-iodoethan-1- one I-471

2-iodo-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)ethan-1-one I-472

2-phenoxy-1-(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-473

1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)-2-phenoxyethan- 1-one I-474

1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)-2-phenoxyethan- 1-one I-475

2-oxo-2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)ethyl methanesulfonate I-476

2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)-2-oxoethyl methanesulfonate I-477

2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepan-1-yl)-2-oxoethyl methanesulfonate I-478

(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1- yl)(oxiran-2-yl)methanone I-479

(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1- yl)(oxiran-2-yl)methanone I-480

oxiran-2-yl(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1- yl)methanone I-481

(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)(3- methyloxiran-2-yl)methanone I-482

(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)(3- methyloxiran-2-yl)methanone I-483

(3-methyloxiran-2-yl)(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1- yl)methanone I-484

methyl 3-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1-carbonyl)oxirane-2-carboxylate I-485

methyl 3-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1-carbonyl)oxirane-2-carboxylate I-486

methyl 3-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1- carbonyl)oxirane-2-carboxylate I-487

oxiran-2-yl(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1- yl)methanone I-488

(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(oxiran- 2-yl)methanone I-489

(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(oxiran- 2-yl)methanone I-490

(3-methyloxiran-2-yl)(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1- yl)methanone I-491

(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(3- methyloxiran-2-yl)methanone I-492

(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(3- methyloxiran-2-yl)methanone I-493

methyl 3-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidine-1-carbonyl)oxirane-2-carboxylate I-494

methyl 3-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidine-1-carbonyl)oxirane-2-carboxylate I-495

methyl 3-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidine-1- carbonyl)oxirane-2-carboxylate I-496

oxiran-2-yl(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1- yl)methanone I-497

(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)(oxiran-2- yl)methanone I-498

(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)(oxiran-2- yl)methanone I-499

(3-methyloxiran-2-yl)(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)methanone I-500

(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)(3- methyloxiran-2-yl)methanone I-501

(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)(3- methyloxiran-2-yl)methanone I-502

methyl 3-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1- carbonyl)oxirane-2-carboxylateI-503

methyl 3-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1- carbonyl)oxirane-2-carboxylateI-504

methyl 3-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepane-1- carbonyl)oxirane-2-carboxylate I-505

(E)-5-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)pent-3- en-2-one I-506

(E)-5-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)pent-3- en-2-one I-507

(E)-5-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)pent-3- en-2-one I-508

(E)-5-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pent-3- en-2-one I-509

(E)-5-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)pent-3- en-2-one I-510

(E)-5-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)pent-3- en-2-one I-511

(E)-5-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)pent-3-en-2-one I-512

(E)-5-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)pent-3-en-2-one I-513

(E)-5-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)pent-3-en- 2-one I-514

2-chloro-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-515

2-chloro-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-516

2-chloro-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-517

2-bromo-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-518

2-bromo-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-519

2-bromo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-520

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-2- iodoethan-1-one I-521

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-2- iodoethan-1-one I-522

2-iodo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-523

2-phenoxy-1-(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-524

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-2- phenoxyethan-1-one I-525

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-2- phenoxyethan-1-one I-526

2-oxo-2-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)ethyl methanesulfonate I-527

2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-2- oxoethyl methanesulfonate I-528

2-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-2- oxoethyl methanesulfonate I-529

2-chloro-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)ethan-1- one I-530

2-chloro-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)ethan-1- one I-531

2-chloro-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1- one I-532

2-bromo-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)ethan-1- one I-533

2-bromo-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)ethan-1- one I-534

2-bromo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1- one I-535

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2- iodoethan-1-one I-536

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2- iodoethan-1-one I-537

2-iodo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1- one I-538

2-phenoxy-1-(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethan-1- one I-539

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2- phenoxyethan-1-one I-540

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2- phenoxyethan-1-one I-541

2-oxo-2-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethyl methanesulfonate I-542

2-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2- oxoethyl methanesulfonate I-543

2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2- oxoethyl methanesulfonate I-544

2-chloro-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)ethan-1- one I-545

2-chloro-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-546

2-chloro-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-547

2-bromo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)ethan-1- one I-548

2-bromo-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-549

2-bromo-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-550

2-iodo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)ethan-1- one I-551

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)-2- iodoethan-1-one I-552

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)-2- iodoethan-1-one I-553

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)-2- phenoxyethan-1-one I-554

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)-2- phenoxyethan-1-one I-555

2-phenoxy-1-(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-556

2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)-2- oxoethyl methanesulfonate I-557

2-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)-2- oxoethyl methanesulfonate I-558

2-oxo-2-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)ethyl methanesulfonate I-559

(E)-2-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidine-1- carbonyl)but-2-enenitrileI-560

(E)-2-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidine-1- carbonyl)but-2-enenitrileI-561

(E)-2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidine-1- carbonyl)but-2-enenitrile I-562

2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidine-1- carbonyl)acrylonitrile I-563

2-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidine-1- carbonyl)acrylonitrile I-564

2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidine-1- carbonyl)acrylonitrile I-565

2-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1- carbonyl)acrylonitrile I-566

2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1- carbonyl)acrylonitrile I-567

2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1- carbonyl)acrylonitrile I-568

2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepane-1- carbonyl)acrylonitrile I-569

2-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepane-1- carbonyl)acrylonitrile I-570

2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepane-1- carbonyl)acrylonitrile I-571

(E)-2-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1- carbonyl)but-2-enenitrileI-572

(E)-2-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1- carbonyl)but-2-enenitrileI-573

(E)-2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepane-1- carbonyl)but-2-enenitrile I-574

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)but-2-yn- 1-one I-575

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)but-2-yn- 1-one I-576

1-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)but-2-yn- 1-one I-577

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2- yn-1-one I-578

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2- yn-1-one I-579

1-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2- yn-1-one I-580

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)prop-2- en-1-one I-581

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)prop-2- en-1-one I-582

1-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)azepan-1-yl)prop-2- en-1-one I-583

1-(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2- en-1-one I-584

1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2- en-1-one I-585

1-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2- en-1-one I-586

(2-chloro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-587

(2-fluoro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-588

(4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-589

(2-chloro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)azepan-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-590

(2-fluoro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)azepan-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-591

(4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)azepan-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-592

2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)acrylonitrile I-593

2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)acrylonitrile I-594

2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)acrylonitrile I-595

2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1- carbonyl)acrylonitrile I-596

2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1- carbonyl)acrylonitrile I-597

2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-1- carbonyl)acrylonitrile I-598

2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)acrylonitrile I-599

2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)acrylonitrile I-600

2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)acrylonitrile I-601

N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-602

N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide I-603

N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4- carboxamide I-604

N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)thiazole-5-carboxamide I-605

N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-1-phenylcyclopropane-1-carboxamide I-606

N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamide I-607

N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)isoquinoline-1-carboxamide I-608

1-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-3-phenylureaI-609

1-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-(pyridin-3-yl)urea I-610

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-methoxyethyl)benzamide I-611

(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(morpholino)methanone I-612

(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(morpholino)methanone I-613

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-morpholinoethyl)benzamide I-614

3-chloro-N-(3-cyanophenyl)-4-(4- (((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)benzamideI-615

(2-chloro-4-(1,2,3,4- tetrahydroisoquinoline-2-carbonyl)phenyl)(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-616

(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone I-617

(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(piperidin-1-yl)methanone I-618

N-benzyl-3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)benzamide I-619

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-620

(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin- 1-yl)methanone I-621

3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-oxaspiro[3.3]heptan- 6-yl)benzamide I-622

(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin- 1-yl)methanone I-623

(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(piperidin-1-yl)methanone I-624

4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-methoxyethyl)benzamide I-625

(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone I-626

4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-morpholinoethyl)benzamide I-627

(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone I-628

N-benzyl-4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)benzamide I-629

4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-630

4-chloro-N-(3-cyanophenyl)-3-(4- (((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)benzamideI-631

4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-632

(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(morpholine-4-carbonyl)phenyl)methanone I-633

4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-634

3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-phenylbenzamideI-635

(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(3-(morpholine-4-carbonyl)phenyl)methanone I-636

4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-methoxyethyl)benzamide I-637

3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-methoxyethyl)benzamide I-638

3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-639

N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide I-640

N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-1-phenylcyclopropane-1-carboxamide I-641

2-(benzyloxy)-N-(3-chloro-4-(4- (((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl)acetamide I-642

N-(3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide I-643

N-(3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)picolinamideI-644

N-(3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran- 4-carboxamide I-645

N-(3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-2-methoxyacetamide I-646

(2-chloro-4-(piperidin-1-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-647

(2-chloro-4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-648

(2-chloro-5-(2- methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-649

(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(3-(2-methoxyethoxy)phenyl)methanone I-650

(2-chloro-4-(phenylamino)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-651

5-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenoxy)-N-methylpicolinamide I-652

N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)benzyl)-2-methoxybenzamide I-653

(racemic)-(2-chloro-4- phenoxyphenyl)(4-((6-(hydroxymethyl)-1-(methylsulfonyl)piperidin-3- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-654

(racemic)-1-(5-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- (hydroxymethyl)-piperidin-1-yl)ethan-1- oneI-655

1-((2S,4R)-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- (hydroxymethyl)pyrrolidin-1-yl)ethan- 1-oneI-656

(2-chloro-4-phenoxyphenyl)(4- (((3R,5S)-5-(hydroxymethyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-657

(4-((((3S,5S)-1-benzyl-5- (hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone

In one embodiment, a compound of the present application (e.g., acompound of any of the formulae or any individual compounds disclosedherein) is a pharmaceutically acceptable salt. In another embodiment, acompound of the present application (e.g., a compound of any of theformulae or any individual compounds disclosed herein) is a solvate. Inanother embodiment, a compound of the present application (e.g., acompound of any of the formulae or any individual compounds disclosedherein) is a hydrate.

The details of the application are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the applicationwill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this application belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this application to refer to oneor more than one (i.e., at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this application to mean either “and” or“or” unless indicated otherwise.

The application also includes pharmaceutical compositions comprising aneffective amount of a compound of Formula (I) and a pharmaceuticallyacceptable carrier.

The term “alkyl,” as used herein, refers to saturated, straight orbranched-chain hydrocarbon radicals containing, in certain embodiments,between one and six carbon atoms. Examples of C₁-C₈ alkyl radicalsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, andn-hexyl radicals.

The term “alkenyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing, in certain embodiments, from twoto six carbon atoms having at least one carbon-carbon double bond. Thedouble bond may or may not be the point of attachment to another group.Alkenyl groups include, but are not limited to, for example, ethenyl,propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

The term “alkoxy” refers to an —O-alkyl radical.

The terms “hal,” “halo,” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “aryl,” as used herein, refers to a mono- or poly-cycliccarbocyclic ring system having one or more aromatic rings, fused ornon-fused, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like.

The term “aralkyl,” as used herein, refers to an alkyl residue attachedto an aryl ring. Examples include, but are not limited to, benzyl,phenethyl and the like.

The term “cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated or partiallyunsaturated carbocyclic ring compound. Examples of C₃-C₈ cycloalkylinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2]octyl. Also contemplated is a monovalent group derived from a monocyclicor polycyclic carbocyclic ring compound having at least onecarbon-carbon double bond by the removal of a single hydrogen atom.Examples of such groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “heteroaryl,” as used herein, refers to a mono- or poly-cyclic(e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ringsystem having at least one aromatic ring, having from five to ten ringatoms of which one ring atoms is selected from S, O, and N; zero, one,or two ring atoms are additional heteroatoms independently selected fromS, O, and N; and the remaining ring atoms are carbon. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “heteroaralkyl” as used herein, refers to an alkyl residueattached to a heteroaryl ring. Examples include, but are not limited to,pyridinylmethyl, pyrimidinylethyl and the like.

The term “heterocyclyl,” or “heterocycloalkyl,” as used herein, refersto a saturated or unsaturated non-aromatic 3-, 4-, 5-, 6-, 7-, or8-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic(fused, bridged, or spiro rings), or 11-, 12, 13, or 14-memberedtricyclic ring system (fused, bridged, or spiro rings), where (i) eachring contains between one and three heteroatoms independently selectedfrom oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) thenitrogen and sulfur heteroatoms may optionally be oxidized, and (iv) thenitrogen heteroatom may optionally be quaternized. Representativeheterocycloalkyl groups include, but are not limited to,[1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl,aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl,2-azaspiro[3.3]heptan-5-amine, 1-azaspiro[3.3]heptan-5-amine,1-oxa-6-azaspiro[3.3]heptan-3-amine, 2-azaspiro[3.3]heptan-6-amine,1-azaspiro[3.3]heptan-6-amine, 6-azaspiro[3.4]octan-2-amine,5-azaspiro[3.4]octan-2-amine, 6-azaspiro[3.4]octan-1-amine,5-azaspiro[3.4]octan-1-amine, 5-oxa-2-azaspiro[3.4]octan-7-amine,7-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide,5-oxa-2-azaspiro[3.4]octan-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane5,5-dioxide, and the like.

The term “alkylamino” refers to a group having the structure, e.g.,NH(C₁-C₆ alkyl), where C₁-C₆ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure, e.g.,N(C₁-C₆ alkyl)₂, where C₁-C₆ alkyl is as previously defined.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

In accordance with the application, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

As described herein, compounds of the application may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the application. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. The terms “optionally substituted”, “optionally substitutedalkyl,” “optionally substituted alkenyl,” “optionally substitutedcycloalkyl,” “optionally substituted cycloalkenyl,” “optionallysubstituted aryl”, “optionally substituted heteroaryl,” “optionallysubstituted aralkyl”, “optionally substituted heteroaralkyl,”“optionally substituted heterocyclyl,” and any other optionallysubstituted group as used herein, refer to groups that are substitutedor unsubstituted by independent replacement of one, two, or three ormore of the hydrogen atoms thereon with substituents including, but notlimited to: —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHS₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

The term “carrier”, as used in this application, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The compounds of the present application may form salts which are alsowithin the scope of this application. Reference to a compound of theFormula herein is understood to include reference to salts thereof,unless otherwise indicated.

Representative “pharmaceutically acceptable salts” include, e.g.,water-soluble and water-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fumerate,fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.

The compounds of the present application, for example, including thepharmaceutically acceptable salts, tautomers, prodrugs, and polymorphsof the compounds, can exist in a solvated form with other solventmolecules or in an unsolvated form.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundsor salts have a tendency to trap a fixed molar ratio of solventmolecules in the crystalline solid state, thus forming a solvate. If thesolvent is water the solvate formed is a hydrate; and if the solvent isalcohol, the solvate formed is an alcoholate. Hydrates are formed by thecombination of one or more molecules of water with one molecule of thesubstance in which the water retains its molecular state as H₂O.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this application, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, ifa compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the application. Individual stereoisomers of the compoundof the application may, for example, be substantially free of otherisomers, or may be admixed, for example, as racemates or with all other,or other selected, stereoisomers. The chiral centers of the presentapplication can have the S or R configuration as defined by the IUPAC1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,”“prodrug” and the like, is intended to equally apply to the salt,solvate, ester and prodrug of enantiomers, stereoisomers, rotamers,tautomers, positional isomers, racemates or prodrugs of the inventivecompounds.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesor as individual enantiomers or diastereomers.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

The compounds of the application may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of theapplication as well as mixtures thereof, including racemic mixtures,form part of the present application. In addition, the presentapplication embraces all geometric and positional isomers. For example,if a compound of the application incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the application. Each compound herein disclosedincludes all the enantiomers that conform to the general structure ofthe compound. The compound may be in a racemic or enantiomerically pureform, or any other form in terms of stereochemistry. The assay resultsmay reflect the data collected for the racemic form, theenantiomerically pure form, or any other form in terms ofstereochemistry.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

In another embodiment of the application, the compound of Formula (I) isan enantiomer. In some embodiments the compound is the (S)-enantiomer.In other embodiments the compound is the (R)-enantiomer. In yet otherembodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.The compound may contain more than one stereocenter.

In another embodiment of the application, the compounds of Formula (I)are diastereomers. In some embodiments, the compounds are the syndiastereomer. In other embodiments, the compounds are the antidiastereomer.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the application may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the application. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the application.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., innucleobases such as guanine, thymine and cytosine), amine-enamine andenamine-imine. For example,(Pyrrolopyrimidinyl)methanone-(Pyrrolopyrimidinyl)methanol tautomericpairs are included in the present application:

The present application relates to a compound of Formula (I) orpharmaceutically acceptable salts thereof, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof,capable of inhibiting BTK, which are useful for the treatment ofdiseases and disorders associated with modulation of a BTK kinase. Theapplication further relates to compounds of Formula (I), orpharmaceutically acceptable salts thereof, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof, whichare useful for inhibiting BTK. In some embodiments, the BTK is wild-typeBTK. In other embodiments, the BTK is a mutant BTK.

Another aspect of the application relates to a compound of Formula (I),wherein the compound inhibits kinase activity of a mutant BTK, such as adrug-resistant mutant BTK harboring a drug-resistance mutation (e.g.,C481S mutation). In some embodiments, the patient or subject does notrespond to a BTK inhibitor or relapses after the treatment with a BTKinhibitor, due to a mutation of BTK kinase (e.g., a C481S mutation) thatprevents target inhibition. In one embodiment, the BTK mutation is aC481S mutation.

In some embodiments, the application provides a compound of Formula (I),wherein the compound is more potent than one or more known BTKinhibitors, including, but not limited to Ibrutinib, GDC-0834, RN486,CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13, atinhibiting the activity of BTK. For example, the compound can be atleast about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about100-fold more potent (e.g., as measured by IC₅₀) than Ibrutinib,GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774,and/or LFM-A13 at inhibiting the activity of the BTK.

In some embodiments, the application provides a compound of Formula (I),wherein the compound is more potent than one or more known BTKinhibitors, including, but not limited to Ibrutinib, GDC-0834, RN486,CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13, atinhibiting the activity of BTK containing one or more mutations asdescribed herein, e.g., C481S. For example, the compound can be at leastabout 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about100-fold more potent (e.g., as measured by IC₅₀) than Ibrutinib,GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774,and/or LFM-A13 at inhibiting the activity of the BTK containing one ormore mutations as described herein. A drug-resistant BTK mutant can havewithout limitation a drug resistance mutation comprising C481S mutation.

Potency of the inhibitor can be determined by IC₅₀ value. A compoundwith a lower IC₅₀ value, as determined under substantially similarconditions, is a more potent inhibitor relative to a compound with ahigher IC₅₀ value.

The compounds of the present application can be converted to N-oxides bytreatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid(m-CPBA) and/or hydrogen peroxides) to afford other compounds of thepresent application. Thus, all shown and claimed nitrogen-containingcompounds are considered, when allowed by valency and structure, toinclude both the compound as shown and its N-oxide derivative (which canbe designated as N→O or N⁺—O⁻). Furthermore, in other instances, thenitrogens in the compounds of the present application can be convertedto N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds canbe prepared by oxidation of the parent amine by an oxidizing agent suchas m-CPBA. All shown and claimed nitrogen-containing compounds are alsoconsidered, when allowed by valency and structure, to cover both thecompounds as shown and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e.,N—OR, wherein R is substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, 3-14-membered carbocycle or 3-14-memberedheterocycle) derivatives.

The term “prodrug,” as used in this application, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of Formula (I), or pharmaceutically acceptable salts,tautomers, solvates, metabolites, polymorphs, analogs or derivativesthereof can be delivered in prodrug form. Thus, the present applicationis intended to cover prodrugs of a compound of Formula (I), or apharmaceutically acceptable salt, tautomer, solvate, metabolite,polymorph, analog or derivative thereof, methods of delivering the sameand compositions containing the same. “Prodrugs” are intended to includeany covalently bonded carriers that release an active parent drug of thepresent application in vivo when such prodrug is administered to amammalian subject. Prodrugs are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of the application wherein ahydroxyl or amino, group is bonded to any group that, when the prodrugof the present application is administered to a mammalian subject, itcleaves to form a free hydroxyl or free amino group, respectively.Examples of prodrugs include, but are not limited to, acetate, formate,and benzoate derivatives of alcohol and amine functional groups in thecompounds of each of the formulae described herein or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

As used herein, the term “analog” refers to a compound that isstructurally similar to another compound but differs slightly incomposition (as in the replacement of one atom by an atom of a differentelement or in the presence of a particular functional group, or thereplacement of one functional group by another functional group). Thus,an analog is a compound that is similar or comparable in function andappearance, but not in structure or origin to the reference compound.

The application also comprehends isotopically-labeled compounds, whichare identical to those recited in the each of the formulae describedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number most commonly found in nature. Examples of isotopes that canbe incorporated into compounds of the application include isotopes ofhydrogen, carbon, nitrogen, fluorine, such as ³H, ¹¹C, ¹⁴C, ²H and ¹⁸F.

Compounds of Formula (I), or pharmaceutically acceptable salts,tautomers, prodrugs, solvates, metabolites, polymorphs, analogs orderivatives thereof, that contain the aforementioned isotopes and/orother isotopes of other atoms are within the scope of the presentapplication. Isotopically-labeled compounds of the present application,for example those into which radioactive isotopes such as ³H, ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areuseful for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are useful in PET (positron emission tomography). PET is usefulin brain imaging. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances, isotopically labeled compounds of Formula (I), orpharmaceutically acceptable salts, tautomers, prodrugs, solvates,metabolites, polymorphs, analogs or derivatives thereof, can generallybe prepared by carrying out the procedures disclosed in the Schemesand/or in the Examples described herein, by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent. In one embodiment, the compound of Formula (I) orpharmaceutically acceptable salts, tautomers, prodrugs, solvates,metabolites, polymorphs, analogs or derivatives thereof, is notisotopically labelled.

The present application relates to a compound which is a modulator ofBTK (wild-type BTK or mutant BTK). In one embodiment, the compound ofthe present application is an inhibitor of BTK (wild-type BTK or mutantBTK).

The term “administer”, “administering”, or “administration” as used inthis application refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug, derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or a composition to the subject, which can form an equivalentamount of active compound within the subject's body.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” or “therapeutically effective amount” when used inconnection with a compound or pharmaceutical composition is an amounteffective for treating or preventing a disease in a subject as describedherein.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The compounds of the present application, or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,can also be used to prevent a disease, condition or disorder. As usedherein, “preventing” or “prevent” describes reducing or eliminating theonset of the symptoms or complications of the disease, condition ordisorder.

The term “disorder” is used in this application to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

As used herein, the term “BTK-mediated” diseases or disorders means anydisease or other deleterious condition in which BTK, or a mutantthereof, is known to play a role. Accordingly, another embodiment of thepresent application relates to treating or lessening the severity of oneor more diseases in which BTK, or a mutant thereof, is known to play arole. Specifically, the present application relates to a method oftreating or lessening the severity of a disease or condition selectedfrom a proliferative disorder or an autoimmune disorder, wherein saidmethod comprises administering to a subject in need thereof a compoundsof Formula (I), or pharmaceutically acceptable salts, tautomers,prodrugs, solvates, metabolites, polymorphs, analogs or derivativesthereof, or a composition according to the present application.

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. Exemplary cell proliferative disorders ofthe application encompass a variety of conditions wherein cell divisionis deregulated. Exemplary cell proliferative disorder include, but arenot limited to, neoplasms, benign tumors, malignant tumors,pre-cancerous conditions, in situ tumors, encapsulated tumors,metastatic tumors, liquid tumors, solid tumors, immunological tumors,hematological tumors, cancers, carcinomas, leukemias, lymphomas,sarcomas, and rapidly dividing cells. The term “rapidly dividing cell”as used herein is defined as any cell that divides at a rate thatexceeds or is greater than what is expected or observed amongneighboring or juxtaposed cells within the same tissue. A cellproliferative disorder includes a precancer or a precancerous condition.A cell proliferative disorder includes cancer. Preferably, the methodsprovided herein are used to treat or alleviate a symptom of cancer. Theterm “cancer” includes solid tumors, as well as, hematologic tumorsand/or malignancies. A “precancer cell” or “precancerous cell” is a cellmanifesting a cell proliferative disorder that is a precancer or aprecancerous condition. A “cancer cell” or “cancerous cell” is a cellmanifesting a cell proliferative disorder that is a cancer. Anyreproducible means of measurement may be used to identify cancer cellsor precancerous cells. Cancer cells or precancerous cells can beidentified by histological typing or grading of a tissue sample (e.g., abiopsy sample). Cancer cells or precancerous cells can be identifiedthrough the use of appropriate molecular markers.

Exemplary non-cancerous conditions or disorders include, but are notlimited to, rheumatoid arthritis; inflammation; autoimmune disease;lymphoproliferative conditions; acromegaly; rheumatoid spondylitis;osteoarthritis; gout, other arthritic conditions; sepsis; septic shock;endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma;adult respiratory distress syndrome; chronic obstructive pulmonarydisease; chronic pulmonary inflammation; inflammatory bowel disease;Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreaticfibrosis; hepatic fibrosis; acute and chronic renal disease; irritablebowel syndrome; pyresis; restenosis; cerebral malaria; stroke andischemic injury; neural trauma; Alzheimer's disease; Huntington'sdisease; Parkinson's disease; acute and chronic pain; allergic rhinitis;allergic conjunctivitis; chronic heart failure; acute coronary syndrome;cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter'ssyndrome; acute synovitis; muscle degeneration, bursitis; tendonitis;tenosynovitis; herniated, ruptures, or prolapsed intervertebral disksyndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonarysarcosis; bone resorption diseases, such as osteoporosis;graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia;AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I orII, influenza virus and cytomegalovirus; and diabetes mellitus.

Exemplary cancers include, but are not limited to, adrenocorticalcarcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer,anorectal cancer, cancer of the anal canal, appendix cancer, childhoodcerebellar astrocytoma, childhood cerebral astrocytoma, basal cellcarcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bileduct cancer, intrahepatic bile duct cancer, bladder cancer, urinarybladder cancer, bone and joint cancer, osteosarcoma and malignantfibrous histiocytoma, brain cancer, brain tumor, brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermaltumors, visual pathway and hypothalamic glioma, breast cancer, bronchialadenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous systemcancer, nervous system lymphoma, central nervous system cancer, centralnervous system lymphoma, cervical cancer, childhood cancers, chroniclymphocytic leukemia, chronic myelogenous leukemia, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, cutaneousT-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome,endometrial cancer, esophageal cancer, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,intraocular melanoma, retinoblastoma, gallbladder cancer, gastric(stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST), germ cell tumor, ovarian germ cell tumor,gestational trophoblastic tumor glioma, head and neck cancer,hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, ocular cancer, islet cell tumors (endocrinepancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer,laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, lip and oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell lung cancer, AIDS-relatedlymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma,Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular(eye) melanoma, merkel cell carcinoma, mesothelioma malignant,mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer ofthe tongue, multiple endocrine neoplasia syndrome, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases,chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma,chronic myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pheochromocytoma, pineoblastoma andsupratentorial primitive neuroectodermal tumors, pituitary tumor, plasmacell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostatecancer, rectal cancer, renal pelvis and ureter, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewingfamily of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterinecancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer(melanoma), merkel cell skin carcinoma, small intestine cancer, softtissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, testicular cancer,throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter and otherurinary organs, gestational trophoblastic tumor, urethral cancer,endometrial uterine cancer, uterine sarcoma, uterine corpus cancer,vaginal cancer, vulvar cancer, and Wilm's Tumor.

Methods for Preparing the Compounds

The compounds of the present application may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the scheme described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of the compounds ofthe present application.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present application includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compound but the individual enantiomers and/ordiastereomers as well. When a compound is desired as a single enantiomeror diastereomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

The compounds of the present application can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, the compounds of the present application can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. The compounds of thepresent application (i.e., a compound of Formula (I)) can be synthesizedby following the steps outlined in General Schemes 1-3 which comprises asequence of assembling intermediates 7-a to 7-i. Starting materials areeither commercially available or made by known procedures in thereported literature or as illustrated.

The general way of preparing compounds of Formula (I) by usingintermediates 7-a, 7-b, 7-c, and 7-d is outlined in General Scheme 1 andfurther illustrated in Example 2. Acylation of 7-a with aroyl chlorideor heteroaroyl chloride 7-b using a lewis acid catalyst (e.g., aluminumchloride (AlCl₃)) and a solvent (e.g., nitrobenzene, toluene, etc.)provides intermediate 7-c. Amination of 7-c with amine 7-d optionallyusing a base (e.g., triethylamine (TEA), pyridine, and/or potassiumcarbonate (K₂CO₃)), optionally in a solvent (e.g., N,N-dimethylformamide(DMF), isopropyl alcohol, etc.) and optionally at elevated temperatureprovides a compound of Formula (I).

X is Cl or O-alkyl

Another general way of preparing compounds of Formula (I) by usingintermediates 7-e, 7-b′, 7-c, and 7-d is outlined in General Scheme 2and further illustrated in Example 99. Acylation of 7-e with aroylchloride or heteroaroyl chloride or alkyl ester 7-b′ using a strong base(e.g., n-butyl lithium) and a solvent (e.g., hexanes, tetrahydrofuran,diethylether, etc.) provides intermediate 7-c. Amination of 7-c withamine 7-d optionally using a base (e.g., triethylamine (TEA), pyridine,and/or potassium carbonate (K₂CO₃)), optionally in a solvent (e.g.,N,N-dimethylformamide (DMF), isopropyl alcohol, etc.) and optionally atelevated temperature provides a compound of Formula (I).

Another general way of preparing compounds of Formula (I) by usingintermediates 7-b, 7-d, 7-f, 7-g, 7-h, and 7-i is outlined in GeneralScheme 3 and further illustrated in Example 141. Acylation of 7-f witharoyl chloride or heteroaroyl chloride 7-b using a lewis acid catalyst(e.g., aluminum chloride (AlCl₃)) and a solvent (e.g., nitrobenzene,toluene, etc.) provides intermediate 7-g. Amination of 7-g with amine7-d optionally using a base (e.g., triethylamine (TEA), pyridine, and/orpotassium carbonate (K₂CO₃)), optionally in a solvent (e.g.,N,N-dimethylformamide (DMF), isopropyl alcohol, etc.) and optionally atelevated temperature provides intermediate 7-h. Amination of 7-h withamine 7-i optionally using a base (e.g., triethylamine (TEA), pyridine,and/or potassium carbonate (K₂CO₃)), optionally in a solvent (e.g.,N,N-dimethylformamide (DMF), isopropyl alcohol, etc.) and optionally atelevated temperature provides a compound of Formula (I).

General Procedure D

To a solution of pyrrolo[2,3-d]pyrimidine (8-A) (1 eq.) in DMF (1mL/0.28 mmol) at room temperature was added potassium carbonate (2 eq.)and SEM-Cl (1.2 eq.). The reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was then poured into 1:1water/EtOAc and partitioned. The aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated to dryness. The residue was purified by flashchromatography on silica gel eluting with 30-100% EtOAc/hexanes toafford the product.

General Procedure E

A suspension of the arylnitro compound (9-A) (1 eq.), ammonium chloride(10 eq. and iron (5 eq) in EtOH (1 mL/0.12 mmol) and water (1 mL/0.25mmol) was heated to 80° C. for 2 hours. Upon cooling to roomtemperature, methanol was added, the reaction mixture was vigorouslystirred for 30 min, filtered through Celite and washed with methanol andEtOAc. The filtrate was concentrated to dryness. The residue wastriturated in water and the solids were collected by filtration, driedunder high vacuum to afford the corresponding arylamine.

General Procedure F

To a solution of the arylamine (10-A) (1 eq.) in DMF (2 mL/0.16 mmol)were added carboxylic acid (1.5 eq.), HATU (1.2 eq.) and DIPEA (2.5 eq.)and the reaction mixture was allowed to stir at room temperature for 18hours or heated to 40-50° C. for 3-90 hours. Upon cooling to roomtemperature, the reaction mixture diluted with aqueous saturated NaHCO₃and ethyl acetate. The layers were partitioned and the aqueous layer wasextracted with ethyl acetate. The combined organic layer were washedwith brine, dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure. The crude product was adsorbed ontosilica gel for purification by ISCO CombiFlash (eluted with 0-10%MeOH/DCM or EtOAc/hexanes) or purified by reverse phase C18 columnchromatography (10-95% acetonitrile in water, 0.1% formic acid) to yieldthe amide product (11-A).

General Procedure G

To a solution of the arylamine (1 eq.) in THF (2 mL/0.343 mmol) wereadded isocyanate (1.2 eq.) and DIPEA (2.5 eq.). The reaction mixture wasallowed to stir at room temperature for 18 hours. The volatiles wereremoved under reduced pressure and the residue was adsorbed in silicagel purification by ISCO CombiFlash eluting with EtOAc/hexanes to yieldthe urea product.

General Procedure H

To a solution of SEM-protected substrate (8-A) (1 eq.) in DCM (1mL/0.044 mmol) was added a solution of HCl (4 N in dioxane, 60-81 eq.).The mixture was heated to 40° C. for 18 hours and concentrated todryness under reduced pressure. The residue was diluted with 10 mL ofDCM/MeOH/NH₄OH (90:9:1) and adsorbed onto silica gel for purification byflash chromatography on silica gel eluting with MeOH/DCM (9:1) andDCM/MeOH/NH₄OH (90:9:1) to yield the deprotected product.

Step 1

To a solution of aryl halide (14-A) in DMA (1 mL/0.12 mmol) was addedzinc dust (0.1 eq.) and zinc cyanide (0.5 eq.). The mixture was bubbledwith nitrogen gas for 10 min, and Pd(PPh₃)₄ (0.05 eq.) was added. Themixture was bubbled again with nitrogen for 10 min and heated to 85° C.overnight. Upon cooling to room temperature, the reaction mixture wasdiluted with EtOAc and water. The layers were partitioned; the aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine, dried over MgSO₄, and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel usingMeOH/DCM to afford the desired material.

Step 2

The benzonitrile substrate (15-A) (1 eq.) was suspended in EtOH (1mL/0.05 mmol) and 2N NaOH (10 eq.) was added. The suspension became aclear yellow solution. The reaction mixture was heated at 85° C.overnight. Upon cooling to room temperature, the pH was adjusted to 6with 1N HCl and the mixture was concentrated to dryness under reducedpressure. The residue was dissolved in DMF to make a stock solution of0.04 M. The mixture was filtered through fritted funnel to remove NaClresidue. The stock solution of the benzoic acid product (0.04 M) wasused as such for subsequent amide coupling without further purification.

Step 3

To the benzoic acid substrate (16-A) (1 eq.) in DMF (0.04 M) was addedamine (1.1 eq.), EDCi (1.2 eq.) and HOAt (1.3 eq.) and the reactionmixture was allowed to stir at room temperature for 3-72 hours. Water(2-5 mL/mmol) was added and the mixture was concentrated to drynessunder reduced pressure. The crude product was adsorbed onto silica gelfor purification by ISCO CombiFlash eluting with 0-10% MeOH/DCM.Purification by reverse phase C18 column chromatography (5-95%acetonitrile in water, 0.1% Formic acid) was also used as an alternativemethod. The product fractions were combined and concentrated to drynessunder reduced pressure to yield the amide product.

Step 3 (Alternative Method)

To the benzoic acid substrate (16-A) (1 eq.) in DMF (0.04 M) was addedamine (1.5-3 eq.), HATU (1.5-2 eq.) and DIPEA (2.5-5 eq.) and thereaction mixture was allowed to stir at room temperature for 18 hours orheated to 60° C. for 18 hours. Water (2-5 mL/mmol) was added and themixture was concentrated to dryness under reduced pressure or thereaction mixture was diluted with aqueous saturated NaHCO₃ and ethylacetate. The layers were partitioned and the aqueous layer was extractedwith ethyl acetate. The combined organic layer were washed with brine,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure. The crude product was adsorbed onto silica gel forpurification by ISCO CombiFlash eluting with 0-10% MeOH/DCM or purifiedby high pressure HPLC system (column: Max-RP C-18, 21×50 mm, 10 μM),10-80% acetonitrile in water, +0.1% formic acid) to yield the amideproduct.

General Procedure I

General Procedure for the Saponification of a Benzoic Ester

The benzoic ester substrate (17-A) (1 eq.) were suspended in THF (1mL/0.2 mmol) and methanol (1 mL/0.2 mmol). A solution of 1N lithiumhydroxide was then added (2 eq.) and left to stir at room temperatureovernight. The reaction crude was neutralized with a 1N aqueous solutionof HCl and was concentrated to dryness. The crude product was used as iswithout further purification.

General Procedure J

A general method for amide formation using an acyl chloride withsilyl-protected aniline substrate followed by desilylation

A solution of(4-amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(23-A) (1 eq) in DCM (1 mL/0.05 mmol) is treated with corresponding acylchloride (1.5 eq) and triethylamine (3 eq) at room temperature for 3 h.The mixture is then concentrated and 4M HCl in dioxane (2 mL/0.05 mmol)is added. The mixture is stirred at 40° C. overnight then concentratedand the residue purified by preparative reverse phase HPLC (gradientfrom 30% to 95% of acetonitrile+0.1% formic acid).

Step 5: Synthesis ofN-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide(I-276)

N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamidewas synthesized according to General Scheme 7, using benzoyl chloride.¹H NMR (DMSO-d₆, 400 MHz): δ 12.90 (bs, 1H), 10.62 (s, 1), 8.85 (bs,1H), 8.29 (s, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.87 (dd,J=8.4 Hz, J=1.8 Hz, 1H), 7.65-7.55 (m, 5H), 4.18-4.10 (m, 2H), 3.45-3.33(m, 3H), 3.18-3.13 (m, 1H), 2.22-2.19 (m, 1H), 1.81-1.75 (m, 1H),1.66-1.56 (m, 1H), 1.44-1.34 (m, 1H). LCMS [M+H]⁺: 506.2.

General Procedure K A General Procedure for Arylamine Formation

The arylfluoride substrate (26-A) (1 eq.) was diluted in NMP (1 mL/1.32mmol). Cyclic amine (1.1 eq.) and potassium carbonate (2 eq.) were addedand the mixture was stirred at 120° C. overnight. The reaction mixturewas allowed to cool to room temperature and was diluted with water. Thecrude mixture was extracted with ethyl acetate (×3) and the combinedorganics were washed with water (×2). Organics were dried over magnesiumsulfate, filtered and concentrated to dryness. The product was purifiedby silica gel chromatography (0-50% ethyl acetate in hexanes).

General Procedure L A General Procedure for Phenol Alkylation

A mixture of phenol (26-B) (1 eq.), 1-chloro-2-methoxyethane (1.5 eq.),potassium carbonate (2 eq.) and sodium iodide (0.2 eq.) in DMF (1mL/0.45 mmol) is heated overnight at 80° C. The reaction mixture is thencooled to room temperature and poured in water, stirred for 15 min andfiltered then dried under high vacuum. The product was used as iswithout further purification.

General Procedure M A General Procedure for Ketone Formation ThroughAryllithium Attack on an Ester

5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3-A) (1 eq.) was dilutedin dry THF (1 mL/0.21 mmol) and was cooled to −78° C. n-BuLi (2.1 eq.)was added dropwise and the temperature was monitored with an internalthermocouple to ensure the reaction temperature never rose above −60° C.The reaction mixture was stirred for 1 hour before the substitutedmethyl benzoate (27-A/B) (1.05 eq.) in dry THF (1 mL/0.9 mmol) was addeddropwise with the internal temperature never exceeding −60° C. Themixture was stirred at −78° C. for 1 hour then quenched with saturatedaqueous Ammonium chloride solution and extracted with ethyl acetate(×3). The combined organic layers were washed with sodium bicarbonateand dried over magnesium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel column chromatography(10-100% ethyl acetate in hexanes).

General Procedure N

One general procedure for formation of a diaryl ether is described.

Fluoropyridine substrate (29-B) (1 eq.), methyl-hydroxy-benzoate (29-A)(1 eq.) and potassium carbonate (1 eq.) were dissolved in DMSO (1 mL/0.3mmol). The mixture was stirred at 120° C. under argon atmosphereovernight. After cooled, the reaction mixture was diluted in water andextracted several times with ethyl acetate. Combined organics werewashed with water and dried over magnesium sulfate and concentratedunder reduced pressure. The product was purified by columnchromatography (0-100% ethyl acetate in hexanes).

General Procedure 0

One general procedure for Boc-deprotection is described.

Boc-protected amine (37-A/B) (1.0 equiv) was dissolved in DCM (1.0mL/mmol) and a 4.0M HCl/Dioxane solution (4.0 equiv) was added. Mixturewas stirred at room temperature for 2.0 h, then concentrated undervacuum. A 1:10 solution of aqueous ammonia in EtOH was added untilcomplete dissolution of the residue. The residue was absorbed ontosilica and purified by normal phase column chromatography to give thepurified amine product.

Step 2: Synthesis of(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(38-A) Step 2′: Synthesis of(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(38-B) General Procedure P One General Procedure for VinysulfonamideFormation.

A solution of 2-chloroethanesulfonyl chloride (1.0 equiv) and Et₃N (1.0equiv) in DCM (18 mL/mmol) cooled to 0° C. was added dropwise to asuspension of secondary amine (38-A/B) (1.0 equiv) and Et₃N (1.0 equiv)in DCM (18 mL/mmol), also cooled to 0° C. After 15 minutes, the reactionmixture was washed with saturated aqueous NaHCO₃ (twice), dried overMgSO₄ and concentrated under vacuum. The residue was purified by normalphase chromatography (75%-100% EtOAc/hexanes).

A mixture of enantiomers, diastereomers, cis/trans isomers resultingfrom the processes described above can be separated into their singlecomponents by chiral salt technique, chromatography using normal phase,reverse phase or chiral column, depending on the nature of theseparation.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 400 MHz.Spectra are given in ppm (δ) and coupling constants, J, are reported inHertz. Tetramethylsilane (TMS) was used as an internal standard. Massspectra were collected using a Waters ZQ Single Quad Mass Spectrometer(ion trap ESI). Purity and low resolution mass spectral data weremeasured using Waters Acquity i-class ultra-performance liquidchromatography (UPLC) system with Acquity Photo Diode Array Detector,Acquity Evaporative Light Scattering Detector (ELSD) and Waters ZQ MassSpectrometer. Data was acquired using Waters MassLynx 4.1 software andpurity characterized by UV wavelength 220 nm, ELSD and ESI. Column:Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.6 mL/min; Solvent A(95/5/0.1 10 mM ammonium formate/acetonitrile/formic acid), Solvent B(95/5/0.09 acetonitrile/water/formic acid); gradient: 5-100% B from 0 to2 min, hold 100% B to 2.2 min, then 5% B at 2.21 min.

Abbreviations used in the following examples and elsewhere herein are:

DIPEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

IPA iso-propyl alcohol

IPE di-isopropyl ether

LC/MS liquid chromatography-mass spectrometry

MeOH methanol

MS mass spectrometry

n-BuOH n-butyl alcohol

NMP N-methyl pyrrolidinone

NMR nuclear magnetic resonance

ppm parts per million

TEA triethylamine

Biological Assays

Radiometric Assay

Enzyme assay using full length recombinant active form of wild-type BTKand BTK-C481S is measured as described previously (Anastassiadis T, etal., Nat. Biotechnol. 29(11):1039-45 (2011)). Compounds are tested inmulti-point dose IC₅₀ mode with several folds serial dilution. BTKkinase activity is assayed in a buffer solution. Compounds are mixedwith kinase (wild-type BTK or mutant BTK), and substrate is added intothe kinase reaction mixture and incubated. The reaction is initiated byadding ATP containing ³³P-ATP into the mixture and incubated. Kinaseactivity is detected by P81 filter-binding ³³P radioisotope basedradiometric method. The raw data is fit to a 4-parameter logistic modelto derive the IC₅₀ value for kinase activity inhibition.

Mobility Shift Assay

Compounds are tested either in the inactive or active BTK assays onCaliper LabChip microfluidic mobility shift assay platform.

Full length unphosphorylated form of BTK expressed in Sf9 cells isemployed to test inhibitory activity in the inactive BTK assay. Theenzyme and increasing concentrations of inhibitor are incubated, and thekinase reaction is initiated by the addition an activation mixturecontaining ATP. The plates are incubated, and after the reaction isstopped, measured.

The active BTK assay consists of phosphorylated form of full length BTK.The assay is performed in a buffer solution utilized in the inactive BTKassay. The enzyme inhibitor complexes is incubated, before the kinaseactivation reaction is initiated. After incubation, the reaction isstopped and the mobility shift is measured as described above for theinactive BTK assay. The data of inactive and active BTK assays is fit toa 4 parameter logistic model to calculate the IC₅₀ value.

Methods of Using the Compounds

Another aspect of the application relates to a method of treating,preventing, inhibiting, or eliminating a disease or disorder associatedwith modulation of BTK (e.g., inhibition of BTK). The method comprisesadministering to a subject in need of a treatment for diseases ordisorders associated with modulation of BTK an effective amount acompound of Formula (I) or a pharmaceutically acceptable salt, solvate,prodrug, stereoisomer, or tautomer thereof or a pharmaceuticalcomposition of a compound of Formula (I). In one embodiment, theBTK-mediated disorder is selected from immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders and neurological disorders. Insome embodiments, the method further comprises administering anadditional therapeutic agent selected from an anti-inflammatory agent,an immunomodulatory agent, chemotherapeutic agent, a neurotropic factor,an agent for treating cardiovascular disease, an agent for treatingliver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, and an agent for treatingimmunodeficiency disorders. In some embodiments, the BTK is wild-typeBTK. In other embodiments, the BTK is mutant BTK (e.g., BTK C481Smutant).

Another aspect of the application relates to a method of treating,preventing, inhibiting, or eliminating a cell proliferative disorder,the method comprising administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof, or a pharmaceutical composition of a compound ofFormula (I). In one embodiment, the cell proliferative disorder is acancer. In some embodiments, the method further comprises administeringan additional therapeutic agent selected from an anti-inflammatoryagent, an immunomodulatory agent, chemotherapeutic agent, a neurotropicfactor, an agent for treating cardiovascular disease, an agent fortreating liver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, and an agent for treatingimmunodeficiency disorders.

Another aspect of the application relates to a method of modulating BTK,the method comprising administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof, or a pharmaceutical composition of a compound ofFormula (I). In one embodiment, modulating BTK is inhibiting BTK. Insome embodiments, the BTK is wild-type BTK. In other embodiments, theBTK is mutant BTK (e.g., BTK C481S mutant).

Another aspect of the application relates to a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, for use in a method of treating a BTK-mediateddisorder. In one embodiment, the disease or disorder is selected fromimmune disorders, cancer, cardiovascular diseases, viral infections,inflammation, metabolism/endocrine function disorders and neurologicaldisorders. In some embodiments, the method further comprisesadministering an additional therapeutic agent selected from ananti-inflammatory agent, an immunomodulatory agent, chemotherapeuticagent, a neurotropic factor, an agent for treating cardiovasculardisease, an agent for treating liver disease, an anti-viral agent, anagent for treating blood disorders, an agent for treating diabetes, andan agent for treating immunodeficiency disorders. In some embodiments,the BTK is wild-type BTK. In other embodiments, the BTK is mutant BTK(e.g., BTK C481S mutant).

In another aspect, the present application relates to a pharmaceuticalcomposition of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,for use in a method of treating a BTK-mediated disorder. In oneembodiment, the disease or disorder is selected from immune disorders,cancer, cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders and neurological disorders. Insome embodiments, the method further comprises administering anadditional therapeutic agent selected from an anti-inflammatory agent,an immunomodulatory agent, chemotherapeutic agent, a neurotropic factor,an agent for treating cardiovascular disease, an agent for treatingliver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, and an agent for treatingimmunodeficiency disorders. In some embodiments, the BTK is wild-typeBTK. In other embodiments, the BTK is mutant BTK (e.g., BTK C481Smutant).

Another aspect of the application relates to a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, for use in a method of treating, preventing,inhibiting, or eliminating a cell proliferative disorder. In oneembodiment, the cell proliferative disorder is a cancer.

In another aspect, the present application relates to a pharmaceuticalcomposition of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,for use in a method of treating, preventing, inhibiting, or eliminatinga cell proliferative disorder. In one embodiment, the cell proliferativedisorder is a cancer.

Another aspect of the application relates to a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, for use in modulating BTK. In one embodiment,modulating BTK is inhibiting BTK. In some embodiments, the BTK iswild-type BTK. In other embodiments, the BTK is mutant BTK (e.g., BTKC481S mutant).

In another aspect, the present application relates to a pharmaceuticalcomposition of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof,for use in modulating BTK. In one embodiment, modulating BTK isinhibiting BTK. In some embodiments, the BTK is wild-type BTK. In otherembodiments, the BTK is mutant BTK (e.g., BTK C481S mutant).

Another aspect of the application relates to the use of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating a BTK-mediated disease or disorder. In one embodiment, thedisease or disorder is selected from immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders and neurological disorders. Insome embodiments, the treatment further comprises administering anadditional therapeutic agent selected from an anti-inflammatory agent,an immunomodulatory agent, chemotherapeutic agent, a neurotropic factor,an agent for treating cardiovascular disease, an agent for treatingliver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, and an agent for treatingimmunodeficiency disorders. In some embodiments, the BTK is wild-typeBTK. In other embodiments, the BTK is mutant BTK (e.g., BTK C481Smutant).

In another aspect, the present application relates to the use of apharmaceutical composition of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof, in the manufacture of a medicament for treating aBTK-mediated disease or disorder. In one embodiment, the disease ordisorder is selected from immune disorders, cancer, cardiovasculardiseases, viral infections inflammation, metabolism/endocrine functiondisorders and neurological disorders. In some embodiments, the treatmentfurther comprises administering an additional therapeutic agent selectedfrom an anti-inflammatory agent, an immunomodulatory agent,chemotherapeutic agent, a neurotropic factor, an agent for treatingcardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, and an agent for treating immunodeficiency disorders.In some embodiments, the BTK is wild-type BTK. In other embodiments, theBTK is mutant BTK (e.g., BTK C481S mutant).

Another aspect of the application relates to the use of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating, preventing, inhibiting, or eliminating a cellproliferative disorder. In one embodiment, the cell proliferativedisorder is a cancer.

In another aspect, the present application relates to the use of apharmaceutical composition of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof, in the manufacture of a medicament for treating,preventing, inhibiting, or eliminating a cell proliferative disorder. Inone embodiment, the cell proliferative disorder is a cancer.

Another aspect of the application relates to the use of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor modulating BTK. In one embodiment, modulating BTK is inhibiting BTK.In some embodiments, the BTK is wild-type BTK. In other embodiments, theBTK is mutant BTK (e.g., BTK C481S mutant).

In another aspect, the present application relates to the use of apharmaceutical composition of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, stereoisomer, ortautomer thereof, in the manufacture of a medicament for modulating BTK.In one embodiment, modulating BTK is inhibiting BTK. In someembodiments, the BTK is wild-type BTK. In other embodiments, the BTK ismutant BTK (e.g., BTK C481S mutant).

In some embodiments of the methods and uses described herein, the canceris selected from breast, ovary, cervix, prostate, testis, genitourinarytract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin,keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma,non-small cell lung carcinoma (NSCLC), small cell carcinoma, lungadenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid,follicular carcinoma, undifferentiated carcinoma, papillary carcinoma,seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma andbiliary passages, kidney carcinoma, pancreatic, myeloid disorders,lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx, lip,tongue, mouth, small intestine, colon-rectum, large intestine, rectum,brain and central nervous system, Hodgkin's leukemia, bronchus, thyroid,liver and intrahepatic bile duct, hepatocellular, gastric,glioma/glioblastoma, endometrial, melanoma, kidney and renal pelvis,urinary bladder, uterine corpus, uterine cervix, multiple myeloma, acutemyelogenous leukemia, chronic myelogenous leukemia, lymphocyticleukemia, chronic lymphoid leukemia (CLL), myeloid leukemia, oral cavityand pharynx, non-Hodgkin lymphoma, melanoma, and villous colon adenoma.

In any of the embodiments of the application, the cancer can be anycancer in any organ, for example, a cancer is selected from the groupconsisting of glioma, thyroid carcinoma, breast carcinoma, small-celllung carcinoma, non-small-cell carcinoma, gastric carcinoma, coloncarcinoma, gastrointestinal stromal carcinoma, pancreatic carcinoma,bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrialcarcinoma, prostate carcinoma, renal carcinoma, anaplastic large-celllymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, andcombinations thereof.

In some embodiments of the methods and uses described herein, thedisease or disorder is an immune disorder. In one embodiment, the immunedisorder is rheumatoid arthritis.

In some embodiments of the methods and uses described herein, thedisease or disorder is systemic and local inflammation, arthritis,inflammation related to immune suppression, organ transplant rejection,allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma,systemic lupus erythematosus, Sjogren's Syndrome, multiple sclerosis,scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura(ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronicobstructive pulmonary disease (COPD), psoriasis.

In one embodiment, methods of treating a disease or disorder associatedwith modulation of BTK including, immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders and neurological disorders,comprise administering to a subject suffering from at least one of saiddiseases or disorder a compound of Formula (I).

The disclosed compound of the application can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

The compound of the application can be administered in therapeuticallyeffective amounts in a combinational therapy with one or moretherapeutic agents (pharmaceutical combinations) or modalities, e.g.,non-drug therapies. For example, synergistic effects can occur withother anti-proliferative, anti-cancer, immunomodulatory oranti-inflammatory substances. In some embodiments, a compound of Formula(I) is administered in combination with an additional therapeutic agentselected from an anti-inflammatory agent, an immunomodulatory agent,chemotherapeutic agent, a neurotropic factor, an agent for treatingcardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, and an agent for treating immunodeficiency disorders.Where the compound of the application is administered in conjunctionwith other therapies, dosages of the co-administered compounds will ofcourse vary depending on the type of co-drug employed, on the specificdrug employed, on the condition being treated and so forth.

Combination therapy includes the administration of the subject compoundin further combination with other biologically active ingredients (suchas, but not limited to, an anti-inflammatory agent, an immunomodulatoryagent, chemotherapeutic agent, a neurotropic factor, an agent fortreating cardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, and an agent for treating immunodeficiency disorders)and non-drug therapies (such as, but not limited to, surgery orradiation treatment). For instance, the compound of the application canbe used in combination with other pharmaceutically active compounds,preferably compounds that are able to enhance the effect of the compoundof the application. The compound of the application can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other drug therapy or treatment modality. Ingeneral, a combination therapy envisions administration of two or moredrugs during a single cycle or course of therapy.

Pharmaceutical Compositions

The present application also provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, prodrug, stereoisomer, or tautomer thereof, incombination with at least one pharmaceutically acceptable excipient orcarrier.

A “pharmaceutical composition” is a formulation containing the compoundof the present application in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or a pharmaceutically acceptablesalt, solvate, prodrug, stereoisomer, or tautomer thereof) in a unitdose of composition is an effective amount and is varied according tothe particular treatment involved. One skilled in the art willappreciate that it is sometimes necessary to make routine variations tothe dosage depending on the age and condition of the patient. The dosagewill also depend on the route of administration. A variety of routes arecontemplated, including oral, pulmonary, rectal, parenteral,transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal,and the like. Dosage forms for the topical or transdermal administrationof a compound of this application include powders, sprays, ointments,pastes, creams, lotions, gels, solutions, patches and inhalants. In oneembodiment, the active compound is mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives, buffersor propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A pharmaceutical compositions of the application are formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the application can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the application may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. The dose chosen should besufficient to constitute effective treatment but not as high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In one embodiment, thedisease or disorder is selected from immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders and neurological disorders. Inanother embodiment, the disease or condition to be treated is cancer. Inanother embodiment, the disease or condition to be treated is a cellproliferative disorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compound (i.e., acompound of Formula (I)) of the present application may be manufacturedin a manner that is generally known, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Pharmaceuticalcompositions may be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers comprising excipients and/orauxiliaries that facilitate processing of the active compound intopreparations that can be used pharmaceutically. Of course, theappropriate formulation is dependent upon the route of administrationchosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compound is delivered in the formof an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compound is formulated intoointments, salves, gels, or creams as generally known in the art.

The active compound can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the application are dictated by anddirectly dependent on the unique characteristics of the active compoundand the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the application vary depending onthe agent, the age, weight, and clinical condition of the recipientpatient, and the experience and judgment of the clinician orpractitioner administering the therapy, among other factors affectingthe selected dosage. Generally, the dose should be sufficient to resultin slowing, and preferably regressing, the growth of the tumors and alsopreferably causing complete regression of the cancer. Dosages can rangefrom about 0.01 mg/kg per day to about 5000 mg/kg per day. An effectiveamount of a pharmaceutical agent is that which provides an objectivelyidentifiable improvement as noted by the clinician or other qualifiedobserver. For example, regression of a tumor in a subject may bemeasured with reference to the diameter of a tumor. Decrease in thediameter of a tumor indicates regression. Regression is also indicatedby failure of tumors to reoccur after treatment has stopped. As usedherein, the term “dosage effective manner” refers to amount of an activecompound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the compound of the present application wherein the parent compoundis modified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines, alkalior organic salts of acidic residues such as carboxylic acids, and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include, but are not limitedto, those derived from inorganic and organic acids selected from2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic,pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic,salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic,sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurringamine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present application alsoencompasses salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same salt.

The compound of the present application can also be prepared as esters,for example, pharmaceutically acceptable esters. For example, acarboxylic acid function group in a compound can be converted to itscorresponding ester, e.g., a methyl, ethyl or other ester. Also, analcohol group in a compound can be converted to its corresponding ester,e.g., an acetate, propionate or other ester.

The compound of the present application can also be prepared asprodrugs, for example, pharmaceutically acceptable prodrugs. The terms“pro-drug” and “prodrug” are used interchangeably herein and refer toany compound which releases an active parent drug in vivo. Sinceprodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc.), the compound of the present application can be delivered inprodrug form. Thus, the present application is intended to coverprodrugs of the presently claimed compound, methods of delivering thesame and compositions containing the same. “Prodrugs” are intended toinclude any covalently bonded carriers that release an active parentdrug of the present application in vivo when such prodrug isadministered to a subject. Prodrugs in the present application areprepared by modifying functional groups present in the compound in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compound. Prodrugs include the compound of thepresent application wherein a hydroxy, amino, sulfhydryl, carboxy orcarbonyl group is bonded to any group that may be cleaved in vivo toform a free hydroxyl, free amino, free sulfhydryl, free carboxy or freecarbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, esters (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl)N-Mannich bases, Schiff bases and enaminonesof amino functional groups, oximes, acetals, ketals and enol esters ofketone and aldehyde functional groups in the compound of theapplication, and the like, See Bundegaard, H., Design of Prodrugs, p1-92, Elsevier, New York-Oxford (1985).

The compound, or pharmaceutically acceptable salts, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof, areadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperintoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecallyand parenterally. In one embodiment, the compound or a pharmaceuticallyacceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof isadministered orally. One skilled in the art will recognize theadvantages of certain routes of administration.

The dosage regimen utilizing the compound is selected in accordance witha variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or pharmaceutically acceptablesalt, tautomer, prodrug, solvate, metabolite, polymorph, analog orderivative thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Techniques for formulation and administration of the disclosed compoundof the application can be found in Remington: the Science and Practiceof Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995).In an embodiment, the compound described herein, and thepharmaceutically acceptable salts, tautomers, prodrugs, solvates,metabolites, polymorphs, analogs or derivatives thereof, are used inpharmaceutical preparations in combination with a pharmaceuticallyacceptable carrier or diluent. Suitable pharmaceutically acceptablecarriers include inert solid fillers or diluents and sterile aqueous ororganic solutions. The compound or pharmaceutically acceptable salts,prodrugs, solvates, metabolites, polymorphs, analogs or derivativesthereof will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present application areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentapplication. The examples do not limit the claimed application. Based onthe present application the skilled artisan can identify and employother components and methodology useful for practicing the presentapplication.

EXAMPLES

The application is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisapplication in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe application is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present application and/orscope of the appended claims.

Example 1:(2-chlorophenyl)-(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-1)

Step 1: Synthesis of(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(2-C)

A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-A, 4.61 g, 30mmol), 2-chlorobenzoyl chloride (2-B, 5.21 mL, 39 mmol), AlCl₃ (12.0 g,90 mmol) and nitrobenzene (30 mL) was heated at 80° C. for 9.5 hrs. Theresultant mixture was poured into ice-water (300 mL) and extracted withEtOAc (×3). The combined extracts were washed with water (×2), saturatedaqueous NaHCO₃, and brine, then dried over anhydrous Na₂SO₄, filteredthrough silica gel pad and concentrated in vacuo. Hexane was added tothe residue. The resulting precipitated solid was collected byfiltration, washed with hexane (×2) and IPE (×2), and then dried at 50°C. to provide(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(2-C, 6.07 g, 22.4 mmol, 75%) as pale brown powder. ¹H-NMR (DMSO-d₆) δ:13.44 (1H, br s), 8.76 (1H, s), 8.03 (1H, s), 7.62-7.55 (3H, m),7.50-7.45 (1H, m). LC/MS: 292 [M+H].

Step 2: Synthesis of(2-chlorophenyl)-(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-1)

A mixture of (2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (2-C, 406 mg, 1.39 mmol), trans-4-aminocyclohexanol (240 mg,2.08 mmol), DIPEA (363 μL, 2.08 mmol) and IPA (12 mL) was stirred at160° C. for 1 h under microwave irradiation followed by concentrationunder reduced pressure. Water was added to the resultant mixture andextracted with EtOAc, and then the extract was washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by column chromatography over SiO₂ with CHCl₃-MeOH, thenthe obtained crude product was suspended in diethyl ether andprecipitate was collected by filtration to give(2-chlorophenyl)-(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-1, 510 mg, 1.38 mmol, 99%) as pale yellow solid. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.71 (1H, d, J=7.9 Hz), 8.24 (1H, s), 7.59-7.55 (3H, m),7.49-7.44 (2H, m), 4.63-4.60 (1H, m), 4.03-4.01 (1H, m), 3.54-3.52 (1H,m), 2.09-2.06 (2H, m), 1.91-1.88 (2H, m), 1.38-1.24 (4H, m). LC/MS: 371[M+H].

Example 2: General Procedure A

Step 1. Intermediate 2-E

A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-A), an aroylchloride or heteroaroyl chloride (2-D, 1.1-1.5 eq.), AlCl₃ (2-5 eq.) andnitrobenzene (0.3-1 M) was heated at 80-100° C. for 1 to 10 hrs. Work-upand/or purification provided the corresponding aryl- orheteroaryl-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (2-E).

Step 2. Compounds of Formula I-X

A mixture of 2-E, a primary amine (2-F, 1-4 eq.), and optionally a base(e.g., TEA, DIPEA, pyridine, and/or K₂CO₃ (1-5 eq.)) in a solvent (e.g.,DMF, NMP, IPA, n-BuOH or neat) was heated (70-160° C.) for 5-50 hrs orheated (100-220° C.) under microwave radiation for 0.5-5 hrs. Work-upand/or purification provided a compound of Formula (I) (aryl- orheteroaryl-[4-(substituted-amino)]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone(I-X)).

The compounds of Formula (I) in Table 1 below were made according toGeneral Procedure A.

TABLE 1 Cmpd No. ¹H NMR and/or LC/MS data I-2 ¹H-NMR (DMSO-d₆) δ: 12.69(1H, s), 8.89 (1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.61-7.54 (3H, m),7.50-7.45 (2H, m), 7.00-6.96 (1H, m), 4.25-4.18 (1H, m), 3.46-3.40 (1H,m), 1.84-1.58 (8H, m), 1.38 (9H, s). LC/MS: 470 [M + H]. I-3 ¹H-NMR(DMSO-d₆) δ: 12.71 (1H, s), 8.83 (1H, d, J = 6.7 Hz), 8.24 (1H, s),7.62-7.53 (3H, m), 7.49-7.45 (2H, m), 7.05 (1H, d, J = 7.3 Hz),4.43-4.34 (1H, m), 3.87-3.78 (1H, m), 2.49-2.40 (1H, m), 2.13-2.03 (1H,m), 1.93-1.84 (1H, m), 1.54-1.67 (2H, m), 1.39-1.48 (1H, m), 1.37 (9H,s). LC/MS: 456 [M + H]. I-4 ¹H-NMR (DMSO-d₆) δ: 8.97 (0.4H, d, J = 7.9Hz), 8.73 (0.6H, d, J = 7.9 Hz), 8.19 (0.4H, s), 8.18 (0.6H, s),7.57-7.53 (3H, m), 7.48-7.43 (1H, m), 7.40 (0.4H, s), 7.39 (0.6H, s),4.58-4.52 (0.4H, m), 4.09-3.98 (0.6H, m), 3.11-3.04 (0.4H, m), 2.73-2.81(0.6H, m), 2.26-1.00 (8H, m). LC/MS: 370 [M + H]. (6:4 diastereomericmixture of I-4). I-13 ¹H-NMR (CDCl₃) δ: 12.36 (1H, br s), 9.01 (1H, d, J= 7.3 Hz), 8.32 (1H, s), 7.43-7.37 (2H, m), 7.30 (2H, t, J = 8.5 Hz),4.41-4.32 (2H, m), 3.71-3.65 (1H, m), 3.61-3.49 (2H, m), 3.31 (1H, t, J= 11.3 Hz), 2.40-2.31 (4H, m), 1.80-1.55 (4H, m). LC/MS: 367 [M + H].I-16 ¹H-NMR (DMSO-d₆) δ: 12.43 (1H, br s), 8.95 (1H, d, J = 7.3 Hz),8.23 (1H, s), 7.45-7.28 (5H, m), 4.09-4.04 (1H, m), 2.73-2.68 (2H, m),2.28 (3H, s), 2.19 (3H, s), 2.17-2.11 (2H, m), 2.04-1.98 (2H, m),1.61-1.53 (2H, m). LC/MS: 350 [M + H]. I-17 ¹H-NMR (DMSO-d₆) δ: 12.63(1H, br s), 8.99 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.45-7.28 (5H, m),4.31-4.23 (1H, m), 3.87-3.81 (2H, m), 3.16-3.05 (2H, m), 2.28 (3H, s),2.04-1.99 (2H, m), 1.47-1.40 (11H, m). LC/MS: 436 [M + H]. I-19 ¹H-NMR(CDCl₃) δ: 12.80 (1H, br s), 9.13 (1H, d, J = 7.3 Hz), 8.31 (1H, s),7.44-7.37 (2H, m), 7.33-7.25 (2H, m), 4.63-4.62 (4H, m), 4.21-4.10 (1H,m), 3.69 (3H, s), 2.42-2.26 (5H, m), 2.14-2.07 (2H, m), 1.54-1.42 (2H,m). LC/MS: 393 [M + H]. I-20 ¹H-NMR (CDCl₃) δ: 12.60 (1H, br s), 9.02(1H, d, J = 7.9 Hz), 8.33 (1H, s), 7.45-7.37 (2H, m), 7.33-7.26 (3H, m),4.45-4.26 (2H, m), 3.29 (1H, t, J = 10.7 Hz), 3.22-3.16 (1H, m),2.40-2.32 (4H, m), 1.84-1.18 (10H, m). LC/MS: 395 [M + H]. I-21 ¹H-NMR(DMSO-d₆) δ: 12.59 (1H, br s), 8.85 (1H, d, J = 7.3 Hz), 8.22 (1H, s),7.45-7.40 (2H, m), 7.35-7.27 (3H, m), 4.61 (1H, d, J = 4.3 Hz),4.02-4.00 (1H, m), 3.55-3.52 (1H, m), 2.27 (3H, s), 2.08-2.06 (2H, m),1.91-1.88 (2H, m), 1.37-1.35 (4H, m). LC/MS: 351 [M + H]. I-22 ¹H-NMR(DMSO-d₆) δ: 12.58 (1H, s), 9.04 (1H, d, J = 7.3 Hz), 8.21 (1H, s), 7.44(2H, t, J = 7.3 Hz), 7.35-7.30 (3H, m), 4.55 (1H, d, J = 3.7 Hz),4.20-4.17 (1H, m), 3.68-3.66 (1H, m), 2.29 (3H, s), 1.81-1.63 (8H, m).LC/MS: 351 [M + H]. I-24 ¹H-NMR (CDCl₃) δ: 8.98 (1H, d, J = 7.3 Hz),8.33 (1H, s), 7.43-7.36 (2H, m), 7.33-7.22 (3H, m), 4.42-4.28 (2H, m),3.95-3.87 (1H, m), 3.36-3.27 (2H, m), 2.40-2.33 (4H, m), 1.79-1.24 (4H,m), 1.18 (3H, d, J = 6.0 Hz). LC/MS: 381 [M + H]. I-26 ¹H-NMR (DMSO-d₆)δ: 9.05 (1H, d, J = 7.3 Hz), 8.19 (1H, s), 7.78 (2H, d, J = 6.7 Hz),7.69 (1H, s), 7.63 (1H, t, J = 7.3 Hz), 7.54 (2H, t, J = 7.6 Hz),4.25-4.20 (1H, m), 2.84-2.77 (1H, m), 1.89-1.80 (2H, m), 1.70-1.60 (4H,m), 1.43-1.53 (2H, m). LC/MS: 336 [M + H]. I-27 ¹H-NMR (CDCl₃) δ: 12.62(1H, br s), 9.31 (1H, t, J = 5.5 Hz), 8.34 (1H, s), 7.43-7.38 (2H, m),7.33-7.25 (3H, m), 4.01-3.49 (9H, m), 2.39 (3H, s). LC/MS: 353 [M + H].I-31 ¹H-NMR (DMSO-d₆) δ: 12.69 (1H, s), 8.88 (1H, d, J = 7.3 Hz), 8.22(1H, s), 7.59-7.56 (3H, m), 7.49-7.45 (2H, m), 4.56 (1H, d, J = 3.1 Hz),4.20-4.18 (1H, m), 3.69-3.66 (1H, m), 1.81-1.63 (8H, m). LC/MS: 371 [M +H]. I-32 ¹H-NMR (DMSO-d₆) δ: 12.71 (1H, s), 8.71 (1H, d, J = 7.9 Hz),8.24 (1H, s), 7.59-7.55 (3H, m), 7.49-7.44 (2H, m), 4.63-4.60 (1H, m),4.03-4.01 (1H, m), 3.54-3.52 (1H, m), 2.09-2.06 (2H, m), 1.91-1.88 (2H,m), 1.38-1.24 (4H, m). LC/MS: 371 [M + H]. I-35 ¹H-NMR (CDCl₃) δ: 11.92(1H, br s), 9.31-9.25 (1H, m), 8.33 (1H, s), 7.42-7.22 (5H, m),4.28-4.13 (2H, m), 3.86-3.78 (1H, m), 3.73-3.57 (3H, m), 3.09 (1H, t, J= 10.7 Hz), 2.38 (3H, s), 2.18-2.10 (1H, m), 1.91-1.84 (1H, m),1.62-1.27 (11H, m). LC/MS: 466 [M + H]. I-38 ¹H-NMR (CDCl₃) δ: 13.48(1H, br s), 8.88 (1H, d, J = 7.9 Hz), 8.31 (1H, s), 7.53-7.36 (4H, m),7.32 (1H, s), 4.41-4.28 (2H, m), 3.95-3.87 (1H, m), 3.37-3.27 (2H, m),2.39-2.30 (1H, m), 1.80-1.66 (3H, m), 1.18 (3H, d, J = 6.1 Hz). LC/MS:401 [M + H]. I-41 ¹H-NMR (DMSO-d₆) δ: 12.57 (1H, s), 9.22 (1H, d, J =7.3 Hz), 8.21 (1H, s), 7.44 (2H, t, J = 6.1 Hz), 7.28-7.36 (3H, m),4.44-4.45 (2H, m), 3.27-3.28 (2H, m), 2.28 (3H, s), 1.50-1.89 (7H, m),1.36-1.39 (2H, m). LC/MS: 365 [M + H]. I-49 ¹H-NMR (CDCl₃) δ: 13.11 (1H,s), 8.86 (1H, d, J = 7.3 Hz), 8.34 (1H, s), 7.54-7.37 (4H, m), 7.31 (1H,s), 4.43-4.26 (2H, m), 3.29 (1H, t, J = 10.4 Hz), 3.22-3.16 (1H, m),2.39-2.31 (1H, m), 1.85-1.55 (4H, m), 1.22 (3H, s), 1.19 (3H, s). LC/MS:415 [M + H]. I-62 ¹H-NMR (DMSO-d₆) δ: 12.69 (1H, br s), 12.15 (1H, brs), 8.92 (1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.61-7.53 (3H, m), 7.50-7.41(2H, m), 4.33-4.26 (1H, m), 2.40-2.46 (1H, m), 1.68-1.91 (8H, m). LC/MS:399 [M + H]. I-76 ¹H-NMR (CDCl₃) δ: 13.17 (1H, br s), 9.19 (1H, d, J =8.0 Hz), 8.26 (1H, s), 7.44-7.38 (2H, m), 7.33-7.26 (3H, m), 4.09-3.98(1H, m), 3.76 (1H, dd, J = 12.2, 2.2 Hz), 3.34 (1H, d, J = 12.2 Hz),2.39 (3H, s), 2.18-2.11 (1H, m), 1.91-1.58 (6H, m), 1.48-1.28 (3H, m).LC/MS: 365 [M + H]. I-77 ¹H-NMR (CDCl₃) δ: 13.23 (1H, s), 9.65 (1H, s),8.24 (1H, s), 7.44-7.25 (5H, m), 3.82 (2H, s), 2.38 (3H, s), 2.15-2.00(4H, m), 1.94-1.70 (4H, m). LC/MS: 351 [M + H]. I-90 ¹H-NMR (CDCl₃) δ:13.32 (1H, br s), 9.08 (1H, d, J = 7.3 Hz), 8.31 (1H, s), 7.44-7.37 (2H,m), 7.33-7.25 (3H, m), 4.51-4.40 (2H, m), 4.09 (1H, dd, J = 10.4, 2.4Hz), 3.80 (3H, s), 3.44-3.35 (1H, m), 2.42-2.34 (4H, m), 2.25-2.18 (1H,m), 1.95-1.72 (2H, m). LC/MS: 395 [M + H]. I-91 ¹H-NMR (CDCl₃) δ: 12.12(1H, br s), 8.88 (1H, d, J = 7.3 Hz), 8.35 (1H, s), 7.53-7.37 (4H, m),7.30 (1H, s), 6.58 (1H, d, J = 4.3 Hz), 5.55 (1H, d, J = 4.3 Hz),4.46-4.30 (2H, m), 3.90 (1H, dd, J = 11.0, 2.4 Hz), 3.35 (1H, t, J =10.4 Hz), 2.43-2.30 (2H, m), 1.84-1.69 (2H, m). LC/MS: 400 [M + H].I-103 ¹H-NMR (DMSO-d₆) δ: 12.67 (1H, s), 8.71 (1H, d, J = 7.3 Hz), 8.22(1H, s), 7.61-7.53 (3H, m), 7.49-7.44 (2H, m), 4.18 (1H, s), 4.00-3.98(1H, m), 1.83-1.81 (2H, m), 1.73-1.60 (4H, m), 1.46-1.40 (2H, m), 1.11(3H, s). LC/MS: 385 [M + H]. I-104 ¹H-NMR (DMSO-d₆) δ: 12.69 (1H, s),8.92 (1H, d, J = 7.9 Hz), 8.23 (1H, s), 7.61-7.53 (3H, m), 7.49-7.45(2H, m), 4.27-4.24 (2H, m), 2.00-1.98 (2H, m), 1.68-1.64 (2H, m),1.57-1.46 (4H, m), 1.15 (3H, s). LC/MS: 385 [M + H]. I-105 ¹H-NMR(CDCl₃) δ: 13.06 (1H, br s), 9.12 (1H, d, J = 7.3 Hz), 8.30 (1H, s),7.43-7.37 (2H, m), 7.33-7.25 (3H, m), 5.84 (1H, br s), 5.55 (1H, br s),4.22-4.10 (1H, m), 2.40-2.30 (5H, m), 2.28-2.03 (3H, m), 1.80-1.66 (2H,m), 1.54-1.42 (2H, m). LC/MS: 378 [M + H]. I-107 ¹H-NMR (DMSO-d₆) δ:12.68 (1H, s), 8.72 (1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.61-7.54 (3H,m), 7.47-7.45 (2H, m), 4.31 (1H, s), 3.98-3.95 (1H, m), 3.28 (3H, s),3.15 (2H, s), 1.87-1.84 (2H, m), 1.64-1.55 (6H, m). LC/MS: 415 [M + H].I-108 ¹H-NMR (DMSO-d₆) δ: 12.67 (1H, s), 8.95 (1H, d, J = 7.3 Hz), 8.23(1H, s), 7.59-7.56 (3H, m), 7.47-7.44 (2H, m), 4.30 (2H, s), 3.29 (3H,s), 3.23 (2H, s), 2.00-1.95 (2H, m), 1.78-1.71 (2H, m), 1.60-1.57 (2H,m), 1.46-1.43 (2H, m). LC/MS: 415 [M + H].

Example 3:(4-((trans-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone (I-5)

Boc deprotection of tert-butylN-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamateprovided Compound I-5. tert-ButylN-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamatewas synthesized according to General Procedure A using tert-butylN-(trans-4-amino-1-cyclohexyl)carbamate. ¹H-NMR (DMSO-d₆) δ: 8.70 (1H,d, J=7.3 Hz), 8.19 (1H, s), 7.59-7.51 (3H, m), 7.47-7.43 (1H, m), 7.38(1H, s), 4.01-3.91 (1H, m), 2.76-2.66 (1H, m), 2.12-2.06 (2H, m),1.89-1.82 (2H, m), 1.21-1.39 (4H, m). LC/MS: 370 [M+H].

Example 4:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone (I-6)

Boc deprotection of Compound I-2 provided Compound I-6. ¹H-NMR (DMSO-d₆)δ: 8.95 (1H, d, J=7.9 Hz), 8.18 (1H, s), 7.60-7.51 (3H, m), 7.49-7.44(1H, m), 7.40 (1H, s), 4.28-4.21 (1H, m), 2.89-2.82 (1H, m), 1.89-1.79(2H, m), 1.72-1.63 (4H, m), 1.45-1.56 (2H, m). LC/MS: 370 [M+H].

Example 5:(4-(((1R,3S)-3-aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone (I-7)

Boc deprotection of Compound I-3 provided Compound I-7. ¹H-NMR (DMSO-d₆)δ: 8.89 (1H, d, J=6.7 Hz), 8.19 (1H, s), 7.59-7.51 (3H, m), 7.48-7.43(1H, m), 7.39 (1H, s), 4.46-4.38 (1H, m), 3.37-3.29 (7H, m), 2.43-2.36(1H, m), 2.12-2.03 (1H, m), 1.89-1.80 (1H, m), 1.74-1.64 (1H, m),1.55-1.46 (1H, m), 1.27-1.35 (1H, m). LC/MS: 356 [M+H].

Example 6:N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(1-methylpiperidin-4-yl)acetamide(I-8)

Acylation of Compound I-5 provided Compound I-8. ¹H-NMR (DMSO-d₆) δ:12.66 (1H, br s), 8.70 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.75 (1H, d,J=7.9 Hz), 7.61-7.53 (3H, m), 7.49-7.44 (2H, m), 4.02-3.93 (1H, m),3.65-3.56 (1H, br m), 2.74-2.66 (2H, m), 2.16-2.10 (5H, m), 1.96 (2H, d,J=6.7 Hz), 1.88-1.76 (3H, m), 1.62-1.52 (3H, m), 1.43-1.27 (4H, m),1.09-1.21 (2H, m). LC/MS: 509 [M+H].

Example 7:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(1-methylpiperidin-4-yl)acetamide(I-9)

Acylation of Compound I-6 provided Compound I-9. ¹H-NMR (DMSO-d₆) δ:8.92 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.86 (1H, d, J=7.9 Hz), 7.62-7.53(3H, m), 7.49-7.45 (2H, m), 4.25-4.19 (1H, m), 3.78-3.71 (1H, m),2.65-2.70 (2H, m), 2.09 (3H, s), 1.99 (2H, d, J=6.7 Hz), 1.80-1.52 (13H,m), 1.19-1.08 (2H, m). LC/MS: 509 [M+H].

Example 8:N-((1S,3R)-3-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclopentyl)-2-(1-methylpiperidin-4-yl)acetamide(I-10)

Acylation of Compound I-7 provided Compound I-10. ¹H-NMR (DMSO-d₆) δ:8.85 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.95 (1H, d, J=7.3 Hz), 7.61-7.54(3H, m), 7.49-7.45 (2H, m), 4.46-4.37 (1H, m), 4.11-4.04 (1H, m),2.69-2.58 (2H, m), 2.49-2.41 (1H, m), 2.16-2.06 (4H, m), 1.96-1.87 (3H,m), 1.76-1.41 (8H, m), 1.05-1.17 (2H, m). LC/MS: 495 [M+H].

Example 9:N-(3-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(1-methylpiperidin-4-yl)acetamide(6:4 diastereomeric mixture) (I-11)

Acylation of Compound I-4 provided Compound I-11. ¹H-NMR (DMSO-d₆) δ:12.68 (1H, br s), 8.92 (0.4H, d, J=7.9 Hz), 8.71 (0.6H, d, J=7.9 Hz),8.24 (0.6H, s), 8.22 (0.4H, s), 7.81-7.76 (1H, m), 7.62-7.53 (3H, m),7.49-7.45 (2H, m), 4.53-4.46 (0.4H, m), 4.14-4.02 (0.6H, m), 4.01-3.91(0.4H, m), 3.75-3.64 (0.6H, m), 2.69-2.65 (2H, m), 2.05-2.23 (4H, m),1.99-1.09 (16H, m). LC/MS: 509 [M+H].

Example 10: tert-butyl(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate (I-12)

Compound I-12 was synthesized according to General Procedure A describedherein above using(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone.

NMR data for(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanoneintermediate: ¹H-NMR (DMSO-d₆) δ: 13.30 (1H, br s), 8.74 (1H, s), 7.94(1H, d, J=3.1 Hz), 7.48-7.44 (2H, m), 7.38-7.35 (1H, m), 7.31-7.26 (1H,m), 2.36 (3H, s).

NMR data for Compound I-12: ¹H-NMR (DMSO-d₆) δ: 12.58 (1H, br s), 9.05(1H, d, J=7.3 Hz), 8.21 (1H, s), 7.46-7.40 (2H, m), 7.37-7.27 (3H, m),6.99-6.94 (1H, m), 4.25-4.19 (1H, m), 3.45-3.39 (1H, m), 2.29 (3H, s),1.87-1.78 (2H, m), 1.58-1.76 (6H, m). LC/MS: 450 [M+H].

Example 11:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-14)

Boc deprotection of Compound I-12 provided Compound I-14. ¹H-NMR(DMSO-d₆) δ: 9.12 (1H, d, J=7.3 Hz), 8.19 (1H, s), 7.44-7.39 (2H, m),7.35-7.27 (3H, m), 4.28-4.21 (1H, m), 2.85-2.78 (1H, m), 2.28 (3H, s),1.89-1.79 (2H, m), 1.71-1.60 (4H, m), 1.54-1.43 (2H, m). LC/MS: 350[M+H].

Example 12:N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide (I-15)

Acylation of Compound I-14 provided Compound I-15. ¹H-NMR (DMSO-d₆) δ:12.61 (1H, s), 9.17 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.55 (1H, d, J=7.9Hz), 7.46-7.41 (2H, m), 7.38-7.27 (3H, m), 4.33-4.25 (1H, m), 3.82-3.74(1H, m), 2.89 (2H, s), 2.16-2.45 (12H, m), 2.02 (3H, s), 1.82-1.63 (8H,m). LC/MS: 490 [M+H].

Example 13:(4-((cis-4-(dimethylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone (I-18)

Reductive alkylation of Compound I-14 with formaline provided CompoundI-18. ¹H-NMR (DMSO-d₆) δ: 12.58 (1H, br s), 9.19 (1H, d, J=7.9 Hz), 8.21(1H, s), 7.45-7.42 (2H, m), 7.37-7.28 (3H, m), 4.37-4.32 (1H, m), 2.27(3H, s), 2.22-2.8 (1H, m) 2.20 (6H, s), 1.82-1.89 (2H, m), 1.60-1.77(6H, m). LC/MS: 378 [M+H].

Example 14:((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)(4-methylpiperazin-1-yl)methanone(I-23)

Synthesis of(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxylicacid using General Procedure A (LC/MS: 381 [M+H]) followed by asubsequent condensation reaction provided Compound I-23. ¹H-NMR (CDCl₃)δ: 9.09 (1H, d, J=7.3 Hz), 8.33 (1H, s), 7.43-7.37 (2H, m), 7.33-7.25(3H, m), 4.47-4.30 (2H, m), 4.22-4.17 (1H, m), 3.80-3.67 (2H, m),3.64-3.53 (2H, m), 3.45-3.38 (1H, m), 2.49-2.37 (8H, m), 2.32 (3H, s),2.10-1.99 (2H, m), 1.83-1.71 (1H, m). LC/MS: 463 [M+H].

Example 15:4-(tert-butyl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)benzamide (I-25)

Acylation of Compound I-14 provided Compound I-25. ¹H-NMR (DMSO-d₆) δ:12.60 (1H, br s), 9.14 (1H, d, J=7.3 Hz), 8.27 (1H, d, J=7.3 Hz), 8.24(1H, s), 7.76-7.78 (2H, m), 7.44 (4H, t, J=5.8 Hz), 7.30-7.35 (3H, m),4.29-4.31 (1H, m), 3.91-3.93 (1H, m), 2.30 (3H, s), 1.96-1.99 (2H, m),1.78-1.79 (6H, m), 1.28 (9H, s). LC/MS: 510 [M+H].

Example 16:2-(4-(4-(tert-butyl)benzoyl)piperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-28) Step 1. tert-butyl4-(2-((4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)amino)-2-oxo-ethyl)piperazine-1-carboxylate(28a)

Acylation of Compound I-14 provided Compound 28a. ¹H-NMR (CDCl₃) δ: 9.45(1H, d, J=7.3 Hz), 8.33 (1H, s), 7.20-7.45 (6H, m), 4.46-4.48 (1H, m),3.99-4.02 (1H, m), 3.39 (4H, s), 3.00 (2H, s), 2.45 (4H, s), 2.39 (3H,s), 1.65-1.99 (8H, m), 1.44 (9H, s). LC/MS: 576 [M+H].

Step 2.N-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-piperazin-1-yl-acetamide(28b)

Boc deprotection of 28a provided Compound 28b. ¹H-NMR (CDCl₃) δ: 9.39(1H, d, J=7.9 Hz), 8.33 (1H, s), 7.41-7.42 (2H, m), 7.25-7.30 (5H, m),4.43-4.46 (1H, m), 3.99-4.02 (1H, m), 2.96-2.98 (2H, m), 2.83-2.84 (4H,m), 2.47-2.49 (4H, m), 2.40 (3H, s), 1.71.91 (8H, m), 1.57-1.59 (5H, m).LC/MS: 476 [M+H].

Step 3.2-(4-(4-(tert-butyl)benzoyl)piperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-28)

Acylation of 28b provided Compound I-28. ¹H-NMR (DMSO-d₆) δ: 12.61 (1H,s), 9.13 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.68 (1H, d, J=7.9 Hz),7.28-7.40 (8H, m), 4.27 (1H, s), 3.78 (1H, s), 3.57 (1H, s), 3.29-3.35(4H, m), 2.97 (2H, s), 2.41-2.51 (4H, m), 2.28 (3H, s), 1.63-1.78 (8H,m), 1.28 (9H, s). LC/MS: 636 [M+H].

Example 17:2-(4-benzoylpiperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-29)

Acylation ofN-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-piperazin-1-yl-acetamideprovided Compound I-29. ¹H-NMR (DMSO-d₆) δ: 12.61 (1H, s), 9.13 (1H, d,J=7.3 Hz), 8.22 (1H, s), 7.69 (1H, d, J=7.3 Hz), 7.28-7.45 (9H, m),4.27-4.29 (1H, m), 3.76-3.79 (1H, m), 3.58-3.60 (1H, m), 3.30-3.32 (4H,m), 2.98 (2H, s), 2.48-2.49 (4H, m), 2.28 (3H, s), 1.66-1.77 (8H, m).LC/MS: 580 [M+H].

Example 18:N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)benzamide(I-30)

Acylation of Compound I-14 provided Compound I-30. ¹H-NMR (DMSO-d₆) δ:12.60 (1H, s), 9.15 (1H, d, J=6.7 Hz), 8.37 (1H, d, J=7.3 Hz), 8.24 (1H,s), 7.84 (2H, d, J=7.3 Hz), 7.35-7.44 (8H, m), 4.29-4.31 (1H, m),3.92-3.94 (1H, m), 2.30 (3H, s), 1.97-1.99 (2H, m), 1.79-1.80 (6H, m).LC/MS: 454 [M+H].

Example 19:N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-33)

Acylation of Compound I-14 provided Compound I-33. ¹H-NMR (DMSO-d₆) δ:12.60 (1H, s), 9.09 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.89 (1H, d, J=7.3Hz), 7.46-7.42 (2H, m), 7.36-7.28 (3H, m), 4.27-4.21 (1H, m), 3.68-3.75(1H, m), 2.29 (3H, s), 1.83-1.59 (11H, m). LC/MS: 392 [M+H].

Example 20:(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)methyl)tetrahydro-2H-pyran-2-carboxamide(I-34)

Condensation of(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxylicacid with the applicable amine provided Compound 1-34. ¹H-NMR (CDCl₃) δ:9.04 (1H, d, J=7.3 Hz), 8.35 (1H, s), 7.44-7.23 (5H, m), 6.72 (1H, t,J=6.4 Hz), 4.46-4.29 (2H, m), 3.99 (2H, dd, J=11.3, 4.0 Hz), 3.90-3.85(1H, m), 3.43-3.29 (3H, m), 3.25-3.12 (2H, m), 2.41-2.32 (5H, m),1.85-1.24 (7H, m). LC/MS: 478 [M+H].

Example 21:(4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexan-1-one(I-36)

Oxidation of Compound I-32 using Dess-Martin Periodinane providedCompound I-36. ¹H-NMR (DMSO-d₆) δ: 12.76 (1H, s), 8.92 (1H, d, J=7.3Hz), 8.29 (1H, s), 7.61-7.53 (3H, m), 7.50-7.45 (2H, m), 4.56-4.54 (1H,m), 2.61-2.53 (1H, m), 2.38-2.28 (5H, m), 1.92-1.89 (2H, m). LC/MS: 369[M+H].

Example 22:(trans-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(4-methylpiperazin-1-yl)methanone(I-37)

Condensation oftrans-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexanecarboxylicacid with the applicable amine provided Compound I-37.trans-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexanecarboxylicacid was synthesized according to General Procedure A. ¹H-NMR (CDCl₃) δ:9.13 (1H, d, J=7.9 Hz), 8.31 (1H, s), 7.43-7.37 (2H, m), 7.33-7.25 (3H,m), 4.25-4.14 (1H, m), 3.69-3.62 (2H, m), 3.57-3.51 (2H, m), 2.60-2.29(13H, m), 1.92-1.41 (6H, m). LC/MS: 461 [M+H].

Example 23:(4-((cis-4-(benzylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-39)

Reductive alkylation of Compound I-14 with benzaldehyde providedCompound I-39. ¹H-NMR (CDCl₃) δ: 9.45 (1H, d, J=7.3 Hz), 8.30 (1H, s),7.20-7.42 (10H, m), 4.40-4.43 (1H, m), 3.84 (2H, s), 2.71-2.73 (1H, m),2.37 (3H, d, J=7.9 Hz), 2.00-2.03 (2H, m), 1.69-1.89 (6H, m). LC/MS: 440[M+H].

Example 24:2-(4-benzylpiperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-40)

Reductive alkylation ofN-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-piperazin-1-yl-acetamidewith benzaldehyde provided Compound I-40. ¹H-NMR (DMSO-d₆) δ: 12.61 (1H,s), 9.17 (1H, d, J=7.9 Hz), 8.23 (1H, s), 7.56 (1H, d, J=7.9 Hz),7.16-7.47 (10H, m), 4.29-4.31 (1H, m), 3.77-3.80 (1H, m), 3.30 (2H, s),2.90 (2H, s), 2.23-2.51 (11H, m), 1.63-1.82 (8H, m). LC/MS: 566 [M+H].

Example 25:(2S,5R)—N—(((S)-1,4-dioxan-2-yl)methyl)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide(I-42)

Condensation of(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxylicacid with the applicable amine provided Compound 1-42. ¹H-NMR (CDCl₃) δ:12.99 (1H, s), 9.09 (1H, d, J=7.3 Hz), 8.34 (1H, s), 7.45-7.26 (5H, m),6.94 (1H, t, J=5.8 Hz), 4.47-4.29 (2H, m), 3.92-3.58 (7H, m), 3.50-3.42(1H, m), 3.37-3.29 (2H, m), 3.25-3.17 (1H, m), 2.41-2.31 (5H, m),1.85-1.60 (2H, m). LC/MS: 480 [M+H].

Example 26:(2-chlorophenyl)(4-((cis-4-(methylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-43)

tert-Butyl N-(cis-4-amino-1-cyclohexyl)carbamate was derivatized to thecorresponding 2-nitrobezenesulfonamide product. N-methylation of thesulfonamide followed by Boc deprotection providedN-(cis-4-amino-1-cyclohexyl)-N-methyl-2-nitrobenzenesulfonamide.

Compound I-43 was then synthesized according to General Procedure A fromreaction ofN-(cis-4-amino-1-cyclohexyl)-N-methyl-2-nitrobenzenesulfonamide with(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.¹H-NMR (DMSO-d₆) δ: 8.91 (1H, d, J=7.3 Hz), 8.20 (1H, s), 7.60-7.53 (3H,m), 7.49-7.42 (2H, m), 4.28-4.22 (1H, m), 2.48-2.48 (1H, m), 2.29 (3H,s), 1.84-1.76 (2H, m), 1.72-1.62 (4H, m), 1.51-1.61 (2H, m). LC/MS: 384[M+H].

Example 27:(2-chlorophenyl)(4-((cis-4-(dimethylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-44)

Reductive alkylation of Compound I-6 with formaline provided CompoundI-44. ¹H-NMR (DMSO-d₆) δ: 12.57 (1H, br s), 9.00 (1H, d, J=7.9 Hz), 8.22(1H, s), 7.61-7.53 (3H, m), 7.50-7.44 (2H, m), 4.37-4.31 (1H, m),2.21-2.17 (7H, m), 1.81-1.89 (2H, m), 1.75-1.62 (6H, m). LC/MS: 398[M+H].

Example 28:N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-45)

Acylation of Compound I-6 provided Compound I-45. ¹H-NMR (DMSO-d₆) δ:12.70 (1H, br s), 8.93 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.90 (1H, d,J=7.9 Hz), 7.62-7.54 (3H, m), 7.50-7.45 (2H, m), 4.28-4.20 (1H, m),3.69-3.77 (1H, m), 1.85-1.58 (11H, m). LC/MS: 412 [M+H].

Example 29:(4-((((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-46)

Boc deprotection of Compound I-35 provided Compound I-46. ¹H-NMR (CDCl₃)δ: 9.32 (1H, t, J=5.5 Hz), 8.33 (1H, s), 7.43-7.25 (5H, m), 4.06-4.00(1H, m), 3.86-3.79 (1H, m), 3.72-3.58 (2H, m), 3.08 (1H, t, J=10.6 Hz),2.92-2.83 (1H, m), 2.38 (3H, s), 2.12-2.04 (1H, m), 1.89-1.22 (5H, m).LC/MS: 366 [M+H].

Example 30:N-(((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide(I-47)

tert-butylN-((3R,6S)-6-(((2-(4-methylpiperazin-1-yl)acetyl)amino)methyl)tetrahydro-2H-pyran-3-yl]carbamatewas synthesized using a typical condensation reaction. LC/MS: 371 [M+H].Boc deprotection of tert-butylN-((3R,6S)-6-(((2-(4-methylpiperazin-1-yl)acetyl)amino)methyl)tetrahydro-2H-pyran-3-yl]carbamatefollowed by halogen displacement using(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone providedCompound I-47. ¹H-NMR (CDCl₃) δ: 12.38 (1H, br s), 9.00 (1H, d, J=6.7Hz), 8.33 (1H, s), 7.57-7.50 (1H, m), 7.45-7.36 (2H, m), 7.33-7.24 (2H,m), 4.40-4.27 (2H, m), 3.68-3.60 (1H, m), 3.51-3.42 (1H, m), 3.32-3.24(1H, m), 3.20-3.11 (1H, m), 3.06 (1H, d, J=16.1 Hz), 3.01 (1H, d, J=16.1Hz), 2.65-2.26 (15H, m), 1.85-1.50 (4H, m). LC/MS: 506 [M+H].

Example 31:(2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)methyl)tetrahydro-2H-pyran-2-carboxamide(I-48)

Condensation of(2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)tetrahydro-2H-pyran-2-carboxylic acid with the applicable amineprovided Compound 1-48. ¹H-NMR (CDCl₃) δ: 13.61 (1H, br s), 8.94 (1H, d,J=7.9 Hz), 8.34 (1H, s), 7.54-7.38 (4H, m), 7.34 (1H, s), 6.73 (1H, t,J=6.1 Hz), 4.45-4.30 (2H, m), 4.02-3.95 (2H, m), 3.88 (1H, dd, J=11.6,1.8 Hz), 3.43-3.29 (3H, m), 3.26-3.13 (2H, m), 2.42-2.32 (2H, m),2.06-1.57 (5H, m), 1.40-1.27 (2H, m). LCMS: 498 [M+H].

Example 32:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-N-methylacetamide(I-50)

Acylation of Compound I-43 provided Compound I-50. ¹H-NMR (DMSO-d₆) δ:12.75 (1H, br s), 9.22 (1H, d, J=7.9 Hz), 8.25 (1H, s), 7.62-7.55 (3H,m), 7.51-7.47 (2H, m), 4.50-4.38 (1.6H, m), 3.69-3.78 (0.4H, m), 2.87(1.8H, s), 2.73 (1.2H, s), 2.06-1.42 (11H, m). LC/MS: 426 [M+H].

Example 33:1-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)pyrrolidin-2-one(I-51) Step 1. 1-(cis-4-aminocyclohexyl)pyrrolidin-2-one (51a)

Acylation of tert-butyl N-(4-aminocyclohexyl)carbamate with4-chlorobutanoyl chloride followed cyclization using sodium hydride Bocdeprotection provided 51a. ¹H-NMR (CD₃OD) δ: 3.94-3.85 (1H, m),3.52-3.46 (3H, m), 2.38 (2H, t, J=8.2 Hz), 2.08-1.64 (11H, m). LC/MS:183 [M+H].

Step 2.1-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)pyrrolidin-2-one(I-51)

Compound I-51 was synthesized using General Procedure A from 51a and(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.¹H-NMR (DMSO-d₆) δ: 12.74 (1H, br s), 9.19 (1H, d, J=7.9 Hz), 8.25 (1H,s), 7.63-7.54 (3H, m), 7.51-7.46 (2H, m), 4.49-4.43 (1H, m), 3.95-3.86(1H, m), 3.38-3.31 (2H, m), 2.20 (2H, t, J=7.9 Hz), 1.99-1.80 (6H, m),1.77-1.67 (2H, m), 1.55-1.47 (2H, m). LC/MS: 438 [M+H].

Example 34:1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one(I-52)

Boc deprotection of Compound I-17 followed by acylation providedCompound I-52. ¹H-NMR (CDCl₃) δ: 12.62-11.97 (1H, m), 9.36-9.32 (1H, m),8.33 (1H, s), 7.49-7.39 (2H, m), 7.33-7.26 (3H, m), 4.49-4.42 (1H, m),4.38-4.28 (1H, m), 3.88-3.82 (1H, m), 3.46-3.34 (1H, m), 3.24-3.18 (1H,m), 2.38 (3H, s), 2.21-2.08 (5H, m), 1.79-1.67 (2H, m). LC/MS: 378[M+H].

Example 35:2-methoxy-1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one(I-53)

Boc deprotection of Compound I-17 followed by acylation providedCompound I-53. ¹H-NMR (CDCl₃) δ: 12.46-11.92 (1H, m), 9.32 (1H, d, J=7.3Hz), 8.33 (1H, s), 7.43-7.38 (2H, m), 7.32-7.26 (3H, m), 4.50-4.42 (1H,m), 4.35-4.29 (1H, m), 4.15 (2H, d, J=2.4 Hz), 3.93-3.87 (1H, m), 3.45(3H, s), 3.41-3.33 (1H, m), 3.28-3.21 (1H, m), 2.38 (3H, s), 2.22-2.15(2H, m), 1.79-1.69 (2H, m). LC/MS: 408 [M+H].

Example 36:3-methoxy-1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)propan-1-one(I-54)

Boc deprotection of Compound I-17 followed by acylation providedCompound I-54. ¹H-NMR (CDCl₃) δ: 9.34 (1H, d, J=7.3 Hz), 8.32 (1H, s),7.43-7.37 (2H, m), 7.32-7.25 (3H, m), 4.46-4.42 (1H, m), 4.37-4.31 (1H,m), 3.93-3.87 (1H, m), 3.74-3.68 (2H, m), 3.42-3.33 (4H, m), 3.26-3.19(1H, m), 2.65 (2H, t, J=6.7 Hz), 2.38 (3H, s), 2.19-2.13 (2H, m),1.81-1.66 (2H, m). LC/MS: 422 [M+H].

Example 37:2-(dimethylamino)-1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethan-1-one(I-55)

Boc deprotection of Compound I-17 followed by acylation providedCompound I-55. 1H-NMR (CDCl₃) δ: 12.96 (1H, br s), 9.32 (1H, d, J=7.9Hz), 8.33 (1H, s), 7.42-7.38 (2H, m), 7.32-7.27 (3H, m), 4.47-4.41 (1H,m), 4.35-4.29 (1H, m), 4.11-4.05 (1H, m), 3.43-3.36 (1H, m), 3.22-3.10(3H, m), 2.38 (3H, s), 2.30 (6H, s), 2.20-2.13 (2H, m), 1.78-1.62 (2H,m). LC/MS: 421 [M+H].

Example 38:(4-((1-(2-methoxyethyl)piperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-56)

Boc deprotection of Compound I-17 followed by acylation providedCompound I-56. ¹H-NMR (D₂O) δ: 8.11 (1H, s), 7.51 (1H, s), 7.39-718 (4H,m), 4.00-3.92 (1H, m), 3.52 (2H, t, J=5.9 Hz), 3.32 (3H, s), 2.74-2.66(2H, m), 2.53 (2H, t, J=5.9 Hz), 2.42-2.34 (2H, m), 2.23 (3H, s),2.00-1.93 (2H, m), 1.69-1.60 (2H, m). LC/MS: 394 [M+H].

Example 39:(4-(((4-aminocyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-57) Step 1. tert-butylN-(4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-cyclohexyl)carbamate(57a)

tert-butylN-(4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-cyclohexyl)carbamate(57a) was synthesized according to General Procedure A from(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone. ¹H-NMR(DMSO-d₆) δ: 12.59 (1H, s), 8.95 (1H, t, J=5.5 Hz), 8.22 (1H, s),7.41-7.45 (2H, m), 7.28-7.35 (3H, m), 6.75 (1H, d, J=6.7 Hz), 3.46-3.48(3H, m), 2.27 (3H, s), 1.73-1.76 (1H, m), 1.50-1.58 (8H, m), 1.38 (9H,s). LC/MS: 464 [M+H].

Step 2.(4-(((4-aminocyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-57)

Boc deprotection of 57a provided Compound I-57. ¹H-NMR (DMSO-d₆) δ: 8.35(1H, s), 7.95 (3H, s), 7.58 (1H, s), 7.44-7.49 (2H, m), 7.31-7.38 (2H,m), 3.58 (3H, t, J=6.4 Hz), 3.23 (1H, m), 2.29 (3H, s), 1.90 (1H, m),1.60-1.73 (8H, m). LC/MS: 364 [M+H].

Example 40:(4-((4-(aminomethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-58) Step 1.2-((4-((5-(2-methyl-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methyl)isoindoline-1,3-dione (58a)

2-((4-((5-(2-methyl-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methyl)isoindoline-1,3-dione (58a) was synthesized according to GeneralProcedure A fromcis-2-((4-aminocyclohexyl)methyl)benzo[c]azolidine-1,3-dione and(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methylphenyl)methanone.¹H-NMR (DMSO-d₆) δ: 1.41-1.51 (2H, m), 1.62-1.65 (4H, m), 1.84-1.85 (3H,m), 2.27 (3H, s), 3.54 (2H, d, J=6.7 Hz), 4.38-4.41 (1H, m), 7.29-7.47(5H, m), 7.77-7.80 (4H, m), 8.20 (1H, s), 9.24 (1H, d, J=7.9 Hz), 12.57(1H, s). LC/MS: 494 [M+H].

Step 2.(4-((4-(aminomethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-58)

Deprotection of the phthalimide group on 58a provided Compound I-58.¹H-NMR (DMSO-d₆) δ: 9.24 (1H, d, J=7.3 Hz), 8.19 (1H, s), 7.41-7.43 (2H,m), 7.28-7.34 (3H, m), 4.41-4.44 (1H, m), 2.47 (2H, d, J=4.9 Hz), 2.27(3H, s), 1.78-1.82 (2H, m), 1.64-1.65 (4H, m), 1.36-1.38 (3H, m). LC/MS:364 [M+H].

Example 41:(4-((4-((4-(tert-butyl)benzyl)amino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-59)

Reductive alkylation of Compound I-14 provided Compound I-59. ¹H-NMR(DMSO-d₆) δ: 9.08 (1H, d, J=7.9 Hz), 8.21 (1H, s), 7.43-7.44 (2H, m),7.25-7.36 (7H, m), 4.23-4.25 (1H, m), 3.69 (2H, s), 2.60-2.62 (1H, m),2.29 (3H, s), 1.82-1.83 (2H, m), 1.64-1.66 (6H, m), 1.26 (9H, s). LC/MS:496 [M+H].

Example 42:(4-((4-((3,5-dichlorobenzyl)amino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-60)

Reductive alkylation of Compound I-14 provided Compound I-60. ¹H-NMR(DMSO-d₆) δ: 12.57 (1H, brs), 9.09 (1H, d, J=7.3 Hz), 8.21 (1H, s), 7.44(5H, dd, J=7.9, 4.9 Hz), 7.28-7.35 (3H, m), 4.23-4.26 (1H, m), 3.75 (2H,s), 2.54-2.56 (1H, m), 2.29 (3H, s), 1.81-1.84 (2H, m), 1.62-1.66 (6H,m). LC/MS: 508 [M+H].

Example 43:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide (I-61)

Acylation of Compound I-43 provided compound I-61. ¹H-NMR (DMSO-d₆) δ:12.73 (1H, br s), 9.21 (1H, d, J=7.9 Hz), 8.24 (1H, s), 7.62-7.55 (3H,m), 7.51-7.46 (2H, m), 4.51-4.42 (1.8H, m), 3.84-3.76 (2.2H, m),3.30-3.23 (2H, m), 2.88 (1.8H, s), 2.75 (1.2H, s), 2.33-2.30 (0.8H, m),2.23-2.20 (1.2H, m), 1.99-1.16 (13H, m). LC/MS: 510 [M+H].

Example 44:cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (I-63)

Amidation of Compound I-62 with the applicable amine provided CompoundI-63. ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 8.95 (1H, d, J=7.3 Hz), 8.23(1H, s), 7.61-7.52 (3H, m), 7.49-7.43 (2H, m), 7.19 (1H, s), 6.72 (1H,s), 4.32 (1H, s), 2.20-2.27 (1H, m), 1.63-1.89 (8H, m). LC/MS: 398[M+H].

Example 45:cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide(I-64)

Amidation of Compound I-62 with the applicable amine provided CompoundI-64. ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 9.03 (1H, d, J=7.3 Hz), 8.23(1H, s), 7.62-7.53 (3H, m), 7.50-7.44 (2H, m), 4.42-4.36 (1H, m), 3.02(3H, s), 2.79 (3H, s), 2.74-2.66 (1H, m), 1.97-1.91 (2H, m), 1.81-1.71(4H, m), 1.56-1.63 (2H, m). LC/MS: 426 [M+H].

Example 46:cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)cyclohexane-1-carboxamide(I-65)

Amidation of Compound I-62 with the applicable amine provided CompoundI-65. ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 8.97 (1H, d, J=7.3 Hz), 8.22(1H, s), 7.67 (1H, d, J=7.9 Hz), 7.62-7.53 (3H, m), 7.49-7.45 (2H, m),4.36-4.31 (1H, m), 3.82-3.66 (3H, m), 3.33-3.27 (2H, m), 2.26-2.19 (1H,m), 1.90-1.60 (10H, m), 1.31-1.41 (2H, m). LC/MS: 482 [M+H].

Example 47:cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)methyl)cyclohexane-1-carboxamide(I-66)

Amidation of Compound I-62 with the applicable amine provided CompoundI-66. ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 8.98 (1H, d, J=7.3 Hz), 8.22(1H, s), 7.72 (1H, t, J=5.8 Hz), 7.61-7.54 (3H, m), 7.49-7.45 (2H, m),4.37-4.32 (1H, m), 3.81-3.75 (2H, m), 3.23-3.16 (2H, m), 2.92 (2H, t,J=6.4 Hz), 2.28-2.23 (1H, m), 1.91-1.49 (10H, m), 1.13-1.07 (2H, m).LC/MS: 496 [M+H].

Example 48:cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(2-(pyridin-3-yl)ethyl)cyclohexane-1-carboxamide(I-67)

Amidation of Compound I-62 with the applicable amine provided CompoundI-67. ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 8.96 (1H, d, J=7.3 Hz),8.40-8.36 (2H, m), 8.22 (1H, s), 7.82 (1H, t, J=5.5 Hz), 7.62-7.53 (4H,m), 7.50-7.45 (2H, m), 7.28 (1H, dd, J=7.6, 4.6 Hz), 4.35-4.29 (1H, m),3.32-3.26 (2H, m), 2.74-2.69 (2H, m), 2.16-2.24 (1H, m), 1.87-1.58 (8H,m). LC/MS: 503 [M+H].

Example 49:cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methylcyclohexane-1-carboxamide(I-68)

Amidation of Compound I-62 with the applicable amine provided CompoundI-68. ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 8.96 (1H, d, J=7.3 Hz), 8.22(1H, s), 7.68-7.64 (1H, m), 7.62-7.54 (3H, m), 7.50-7.45 (2H, m),4.36-4.30 (1H, m), 2.55 (3H, d, J=4.9 Hz), 2.19-2.26 (1H, m), 1.89-1.62(8H, m). LC/MS: 412 [M+H].

Example 50:(2-chlorophenyl)(4-((cis-4-(pyrrolidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-69)

Reductive amination of Compound I-36 provided Compound I-69. ¹H-NMR(DMSO-d₆) δ: 8.89 (1H, d, J=7.9 Hz), 8.22 (1H, s), 7.61-7.53 (3H, m),7.49-7.45 (2H, m), 4.28-4.26 (1H, m), 3.46-3.33 (4H, m), 2.13-2.10 (1H,m), 1.81-1.69 (12H, m). LC/MS: 424 [M+H].

Example 51:(4-((cis-4-(azetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone(I-70)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-70. ¹H-NMR (DMSO-d₆) δ: 12.65 (1H, br s), 8.85 (1H,d, J=7.3 Hz), 8.21 (1H, s), 7.62-7.54 (3H, m), 7.49-7.44 (2H, m),4.21-4.20 (1H, m), 3.07-3.06 (4H, m), 2.14-2.12 (1H, m), 1.94-1.87 (2H,m), 1.72-1.68 (4H, m), 1.53-1.36 (4H, m). LC/MS: 410 [M+H].

Example 52:(4-((trans-4-(azetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone(I-71)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-71. ¹H-NMR (DMSO-d₆) δ: 8.72 (1H, d, J=7.3 Hz), 8.23(1H, s), 7.59-7.54 (3H, m), 7.48-7.45 (2H, m), 4.00-3.99 (1H, m), 3.08(4H, t, J=7.0 Hz), 2.08-2.05 (3H, m), 1.93-1.87 (2H, m), 1.78-1.75 (2H,m), 1.33-1.27 (2H, m), 1.11-1.05 (2H, m). LC/MS: 410 [M+H].

Example 53:N-(4-(tert-butyl)benzyl)-2-methyl-2-((cis-4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)cyclohexyl)amino)propanamide (I-72) Step 1.2-bromo-N-[(4-tert-butylphenyl)methyl]-2-methyl-propanamide (72a)

Acylation of 4-tert-butylbenzylamine with 2-bromo-2-methylpropanoic acidchloride provided2-bromo-N-[(4-tert-butylphenyl)methyl]-2-methyl-propanamide (72a).¹H-NMR (CDCl₃) δ: 7.38 (2H, d, J=7.9 Hz), 7.23 (2H, d, J=7.9 Hz), 6.99(1H, br s), 4.44 (2H, d, J=6.1 Hz), 2.00 (6H, s), 1.32 (9H, s). LC/MS:312 [M+H].

Step 2.N-(4-(tert-butyl)benzyl)-2-methyl-2-((cis-4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)cyclohexyl)amino)propanamide (I-72)

Alkylation of Compound I-57 with2-bromo-N-[(4-tert-butylphenyl)methyl]-2-methyl-propanamide (72a)provided Compound I-72. ¹H-NMR (CDCl₃) δ: 9.17 (1H, t, J=4.9 Hz), 8.32(1H, s), 7.83 (1H, t, J=5.5 Hz), 7.23-7.36 (9H, m), 4.36 (2H, d, J=5.5Hz), 3.55 (2H, t, J=6.1 Hz), 2.80 (1H, s), 3.35 (1H, m), 2.36 (3H, s),1.24-1.88 (23H, m). LC/MS: 595 [M+H].

Example 54:N-benzyl-2-methyl-2-((cis-4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)cyclohexyl)amino)propanamide (I-73)

Alkylation of Compound I-57 provided Compound I-73. ¹H-NMR (CDCl₃) δ:9.17 (1H, t, J=5.2 Hz), 8.32 (1H, s), 7.87 (1H, t, J=6.1 Hz), 7.19-7.42(10H, m), 4.38 (2H, d, J=6.1 Hz), 3.54 (2H, t, J=6.1 Hz), 2.80 (1H, s),2.37 (3H, s), 1.40-1.89 (9H, m), 1.34 (6H, s). LC/MS: 539 [M+H].

Example 55:N-(cis-4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)cyclohexyl)benzamide (I-74)

Acylation of Compound I-57 provided Compound I-74. ¹H-NMR (DMSO-d₆) δ:12.60 (1H, s), 8.98 (1H, t, J=5.5 Hz), 8.23 (1H, s), 8.13 (1H, d, J=7.3Hz), 7.84-7.83 (2H, m), 7.52-7.28 (8H, m), 3.97 (1H, m), 3.58 (2H, t,J=6.4 Hz), 2.27 (3H, s), 1.91-1.57 (9H, m). LC/MS: 468 [M+H].

Example 56:N-((cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methyl)benzamide (I-75)

Acylation of Compound I-58 provided Compound I-75. ¹H-NMR (DMSO-d₆) δ:12.58 (1H, s), 9.24 (1H, d, J=7.3 Hz), 8.50 (1H, t, J=5.8 Hz), 8.22 (1H,s), 7.83-7.82 (2H, m), 7.51-7.29 (8H, m), 4.43-4.40 (1H, m), 3.20 (2H,t, J=6.4 Hz), 2.29 (3H, s), 1.86-1.67 (7H, m), 1.47-1.44 (2H, m). LC/MS:468 [M+H].

Example 57:(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone(I-78)

Amidation of Compound I-62 provided Compound I-78. ¹H-NMR (DMSO-d₆) δ:12.68 (1H, br s), 9.04 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.62-7.54 (3H,m), 7.49-7.45 (2H, m), 4.42-4.37 (1H, m), 3.59-3.40 (8H, m), 2.74-2.66(1H, m), 1.95-1.90 (2H, m), 1.84-1.69 (4H, m), 1.57-1.63 (2H, m). LC/MS:468 [M+H].

Example 58:(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)((2S,6R)-2,6-dimethylmorpholino)methanone(I-79)

Amidation of Compound I-62 provided Compound I-79. ¹H-NMR (DMSO-d₆) δ:12.68 (1H, s), 9.03 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.61-7.54 (3H, m),7.49-7.45 (2H, m), 4.43-4.38 (1H, m), 4.25 (1H, d, J=12.8 Hz), 3.86 (1H,d, J=13.4 Hz), 3.51-3.35 (2H, m), 2.79-2.67 (2H, m), 2.17 (1H, t, J=11.9Hz), 1.97-1.51 (8H, m), 1.04-1.13 (6H, m). LC/MS: 496 [M+H].

Example 59:(4-((cis-4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone(I-80)

Amidation of Compound I-62 provided Compound I-80. ¹H-NMR (DMSO-d₆) δ:12.67 (1H, br s), 9.03 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.62-7.54 (3H,m), 7.50-7.45 (2H, m), 4.41-4.37 (1H, m), 4.32-4.28 (2H, m), 3.95 (1H,d, J=12.8 Hz), 3.64 (1H, d, J=12.2 Hz), 3.31-3.22 (2H, m), 2.76-2.62(2H, m), 1.99-1.50 (12H, m). LC/MS: 494 [M+H].

Example 60:(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(3-hydroxyazetidin-1-yl)methanone (I-81)

Amidation of Compound I-62 provided Compound I-81. ¹H-NMR (DMSO-d₆) δ:12.68 (1H, br s), 8.98 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.61-7.54 (3H,m), 7.49-7.45 (2H, m), 5.69 (1H, d, J=6.1 Hz), 4.46-4.39 (1H, m), 4.34(2H, t, J=7.6 Hz), 3.99 (1H, dd, J=9.5, 7.0 Hz), 3.88 (1H, dd, J=8.5,4.3 Hz), 3.54 (1H, dd, J=9.8, 4.3 Hz), 2.38-2.31 (1H, m), 1.55-1.93 (8H,m). LC/MS: 454 [M+H].

Example 61:(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(4-methylpiperazin-1-yl)methanone (I-82)

Amidation of Compound I-62 provided Compound I-82. ¹H-NMR (DMSO-d₆) δ:12.68 (1H, br s), 9.03 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.62-7.54 (3H,m), 7.50-7.45 (2H, m), 4.42-4.37 (1H, m), 3.52-3.39 (4H, m), 2.74-2.66(1H, m), 2.35-2.16 (7H, m), 1.94-1.89 (2H, m), 1.80-1.70 (4H, m),1.62-1.55 (2H, m). LC/MS: 481 [M+H].

Example 62:(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)((3S,5R)-3,5-dimethylpiperazin-1-yl)methanone (I-83)

Amidation of Compound I-62 provided Compound I-83. ¹H-NMR (CDCl₃) δ:9.30 (1H, d, J=6.7 Hz), 8.33 (1H, s), 7.49-7.34 (4H, m), 7.25 (1H, s),4.56-4.42 (2H, m), 3.72 (1H, d, J=11.5 Hz), 2.84-2.57 (4H, m), 2.23-2.01(5H, m), 1.84-1.68 (4H, m), 1.04-1.13 (6H, m). LC/MS: 495 [M+H].

Example 63:N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide (I-84)

Acylation of Compound I-5 provided Compound I-84. ¹H-NMR (DMSO-d₆) δ:12.69 (1H, br s), 8.70 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.78 (1H, d,J=7.9 Hz), 7.61-7.53 (3H, m), 7.49-7.45 (2H, m), 4.03-3.95 (1H, m),3.63-3.54 (1H, m), 2.15-2.10 (2H, m), 1.90-1.85 (2H, m), 1.27-1.44 (4H,m). LC/MS: 412 [M+H].

Example 64:(S)—N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxypropanamide (I-85)

Acylation of Compound I-6 provided Compound I-85. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, br s), 8.96 (1H, d, J=6.7 Hz), 8.24 (1H, s), 7.62-7.53 (3H,m), 7.49-7.43 (3H, m), 5.40-5.34 (1H, m), 4.31-4.25 (1H, m), 3.99-3.93(1H, m), 3.76-3.70 (1H, m), 1.59-1.84 (8H, m), 1.19 (3H, d, J=6.7 Hz).LC/MS: 442 [M+H].

Example 65:(R)—N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxypropanamide (I-86)

Acylation of Compound I-6 provided Compound I-86. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.62-7.54 (3H, m),7.49-7.43 (3H, m), 5.37 (1H, d, J=5.5 Hz), 4.31-4.25 (1H, m), 3.99-3.93(1H, m), 3.78-3.69 (1H, m), 1.59-1.85 (8H, m), 1.19 (3H, d, J=6.7 Hz).LC/MS: 442 [M+H].

Example 66:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-methoxyacetamide (I-87)

Acylation of Compound I-6 provided Compound I-87. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.66 (1H, d, J=7.9Hz), 7.62-7.54 (3H, m), 7.50-7.46 (2H, m), 4.31-4.25 (1H, m), 3.76-3.80(3H, m), 3.28 (3H, s), 1.87-1.64 (8H, m). LC/MS: 442 [M+H].

Example 67:(2-chlorophenyl)(4-((cis-4-(3-hydroxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-88)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-88.

¹H-NMR (DMSO-d₆) δ: 12.67 (1H, s), 8.84 (1H, d, J=7.9 Hz), 8.22 (1H, s),7.60-7.55 (3H, m), 7.48-7.44 (2H, m), 5.22 (1H, d, J=6.1 Hz), 4.21-4.12(2H, m), 3.49 (2H, t, J=6.7 Hz), 2.65-2.63 (2H, m), 2.13-2.10 (1H, m),1.72-1.66 (4H, m), 1.55-1.46 (4H, m). LC/MS: 426 [M+H].

Example 68:(2-chlorophenyl)(4-((trans-4-(3-hydroxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-89)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-89. ¹H-NMR (DMSO-d₆) δ: 8.71 (1H, d, J=7.3 Hz), 8.23(1H, s), 7.61-7.53 (3H, m), 7.48-7.45 (2H, m), 5.23 (1H, d, J=6.7 Hz),4.12 (1H, dd, J=12.5, 6.4 Hz), 4.00-3.99 (1H, m), 3.48 (2H, t, J=6.7Hz), 2.68 (2H, t, J=6.7 Hz), 2.07-2.03 (3H, m), 1.78 (2H, d, J=9.8 Hz),1.31 (2H, dd, J=22.9, 9.5 Hz), 1.13-1.03 (2H, m). LC/MS: 426 [M+H].

Example 69:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propionamide (I-92)

Acylation of Compound I-6 provided Compound I-92. ¹H-NMR (DMSO-d₆) δ:12.70 (1H, s), 8.93 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.81 (1H, d, J=7.3Hz), 7.62-7.54 (3H, m), 7.50-7.45 (2H, m), 4.27-4.22 (1H, m), 3.69-3.76(1H, m), 2.08 (2H, q, J=7.5 Hz), 1.83-1.59 (8H, m), 0.97 (3H, t, J=7.6Hz). LC/MS: 426 [M+H].

Example 70:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)isobutyramide (I-93)

Acylation of Compound I-6 provided Compound I-93. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.93 (1H, d, J=6.7 Hz), 8.24 (1H, s), 7.76 (1H, d, J=7.3Hz), 7.62-7.53 (3H, m), 7.50-7.46 (2H, m), 4.27-4.20 (1H, m), 3.75-3.68(1H, m), 2.38-2.46 (1H, m), 1.56-1.87 (8H, m), 0.95 (6H, d, J=6.7 Hz).LC/MS: 440 [M+H].

Example 71:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)cyclopropanecarboxamide (I-94)

Acylation of Compound I-6 provided Compound I-94. ¹H-NMR (DMSO-d₆) δ:12.70 (1H, s), 8.95 (1H, d, J=7.9 Hz), 8.24 (1H, s), 8.11 (1H, d, J=7.3Hz), 7.62-7.54 (3H, m), 7.50-7.46 (2H, m), 4.29-4.21 (1H, m), 3.78-3.71(1H, m), 1.84-1.61 (9H, m), 0.56-0.67 (4H, m). LC/MS: 438 [M+H].

Example 72:4-methyl-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)benzamide(I-95)

Acylation of Compound I-14 provided Compound I-95. ¹H-NMR (DMSO-d₆) δ:12.60 (1H, s), 9.15 (1H, d, J=6.7 Hz), 8.27 (1H, d, J=6.7 Hz), 8.24 (1H,s), 7.76 (2H, d, J=8.5 Hz), 7.44-7.42 (2H, m), 7.37-7.28 (3H, m), 7.23(2H, d, J=7.9 Hz), 4.32-4.29 (1H, m), 3.93-3.90 (1H, m), 2.33 (3H, s),2.30 (3H, s), 1.98 (2H, d, J=9.2 Hz), 1.78 (6H, d, J=4.9 Hz). LC/MS: 468[M+H].

Example 73:3-methyl-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)benzamide(I-96)

Acylation of Compound I-14 provided Compound I-96. ¹H-NMR (DMSO-d₆) δ:12.60 (1H, s), 9.15 (1H, d, J=6.7 Hz), 8.30 (1H, d, J=7.3 Hz), 8.24 (1H,s), 7.65-7.62 (2H, m), 7.45-7.42 (2H, m), 7.35-7.30 (5H, m), 4.32-4.29(1H, m), 3.93-3.90 (1H, m), 2.33 (3H, s), 2.30 (3H, s), 1.99-1.97 (2H,m), 1.79-1.78 (6H, m). LC/MS: 468 [M+H].

Example 74:2-methyl-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)benzamide(I-97)

Acylation of Compound I-14 provided Compound I-97. ¹H-NMR (DMSO-d₆) δ:12.58 (1H, s), 9.08 (1H, d, J=7.3 Hz), 8.37 (1H, d, J=7.3 Hz), 8.23 (1H,s), 7.42-7.40 (2H, m), 7.35-7.16 (7H, m), 4.28-4.25 (1H, m), 3.95-3.92(1H, m), 2.31 (3H, s), 2.27 (3H, s), 1.91-1.89 (2H, m), 1.81-1.79 (6H,m). LC/MS: 468 [M+H].

Example 75:(S)—N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-methoxypropanamide (I-98)

Acylation of Compound I-6 provided Compound I-98. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.94 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.75 (1H, d, J=7.3Hz), 7.62-7.53 (3H, m), 7.50-7.45 (2H, m), 4.30-4.23 (1H, m), 3.68-3.80(2H, m), 3.20 (3H, s), 1.61-1.87 (8H, m), 1.18 (3H, d, J=6.7 Hz). LC/MS:456 [M+H].

Example 76:(R)—N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-methoxypropanamide (I-99)

Acylation of Compound I-6 provided Compound I-99. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.75 (1H, d, J=7.3Hz), 7.62-7.54 (3H, m), 7.50-7.46 (2H, m), 4.30-4.23 (1H, m), 3.78-3.68(2H, m), 3.20 (3H, s), 1.60-1.89 (8H, m), 1.18 (3H, d, J=6.7 Hz). LC/MS:456 [M+H].

Example 77:(S)—N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)tetrahydrofuran-2-carboxamide (I-100)

Acylation of Compound I-6 provided Compound I-100. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.95 (1H, d, J=6.7 Hz), 8.23 (1H, d, J=5.5 Hz), 7.62-7.54(4H, m), 7.50-7.46 (2H, m), 4.19-4.30 (2H, m), 3.89-3.83 (1H, m),3.75-3.69 (2H, m), 2.11-2.01 (1H, m), 1.87-1.63 (11H, m). LC/MS: 468[M+H].

Example 78:(R)—N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)tetrahydrofuran-2-carboxamide (I-101)

Acylation of Compound I-6 provided Compound I-101. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.63-7.54 (4H, m),7.50-7.46 (2H, m), 4.30-4.19 (2H, m), 3.89-3.83 (1H, m), 3.75-3.69 (2H,m), 2.02-2.11 (1H, m), 1.87-1.63 (11H, m). LC/MS: 468 [M+H].

Example 79:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1-hydroxycyclopropane-1-carboxamide (I-102)

Acylation of Compound I-6 provided Compound I-102. ¹H-NMR (DMSO-d₆) δ:12.71 (1H, s), 8.98 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.62-7.54 (3H, m),7.50-7.42 (3H, m), 6.29 (1H, s), 4.35-4.27 (1H, m), 3.80-3.71 (1H, m),1.66-1.85 (8H, m), 1.01 (2H, q, J=3.9 Hz), 0.81 (2H, q, J=3.9 Hz).LC/MS: 454 [M+H].

Example 80:(S)—N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxy-N-methylpropanamide (I-106)

Acylation of Compound I-43 provided Compound I-106. ¹H-NMR (DMSO-d₆) δ:12.34 (1H, br s), 9.05 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.57-7.44 (4H,m), 7.34 (1H, s), 4.54-4.33 (3H, m), 2.86 (3H, s), 2.05-1.91 (5H, m),1.80-1.70 (2H, m), 1.49-1.59 (2H, m), 1.20 (3H, d, J=6.1 Hz). LC/MS: 442[M+H].

Example 81:(2-chlorophenyl)(4-((cis-4-(3-methoxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-109)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-109. ¹H-NMR (DMSO-d₆) δ: 12.69 (1H, s), 8.85 (1H, d,J=7.9 Hz), 8.22 (1H, s), 7.59-7.57 (3H, m), 7.49-7.45 (2H, m), 4.21 (1H,s), 3.95-3.90 (1H, m), 3.48 (2H, t, J=6.7 Hz), 3.14 (3H, s), 2.71 (2H,t, J=6.7 Hz), 2.14 (1H, s), 1.72-1.67 (4H, m), 1.56-1.46 (4H, m). LC/MS:440 [M+H].

Example 82:(2-chlorophenyl)(4-((trans-4-(3-methoxyazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-110)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-110. ¹H-NMR (DMSO-d₆) δ: 12.69 (1H, br s), 8.72 (1H,d, J=7.3 Hz), 8.23 (1H, s), 7.59-7.55 (3H, m), 7.48-7.43 (2H, m),4.04-3.99 (1H, m), 3.94-3.88 (1H, m), 3.49-3.43 (2H, m), 3.14 (3H, s),2.76 (2H, t, J=6.7 Hz), 2.10-2.02 (3H, m), 1.79 (2H, d, J=10.4 Hz),1.33-1.26 (2H, m), 1.12-1.05 (2H, m). LC/MS: 440 [M+H].

Example 83:(2-chlorophenyl)(4-((cis-4-(3-hydroxy-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-111)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-111. ¹H-NMR (DMSO-d₆) δ: 12.69 (1H, s), 8.87 (1H, d,J=7.3 Hz), 8.22 (1H, s), 7.59-7.56 (3H, m), 7.49-7.45 (2H, m), 5.08 (1H,s), 4.24 (1H, s), 3.17-3.14 (2H, m), 2.81-2.78 (2H, m), 2.13 (1H, s),1.79-1.76 (2H, m), 1.68-1.63 (2H, m), 1.55-1.53 (2H, m), 1.45-1.43 (2H,m), 1.33 (3H, s). LC/MS: 440 [M+H].

Example 84:(2-chlorophenyl)(4-((trans-4-(3-hydroxy-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-112)

Reductive amination of Compound I-36 and subsequent isomer separationprovided Compound I-112. ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 8.70 (1H,d, J=7.3 Hz), 8.23 (1H, s), 7.59-7.54 (3H, m), 7.49-7.44 (2H, m), 5.09(1H, s), 3.99 (1H, d, J=6.7 Hz), 3.16 (2H, d, J=7.3 Hz), 2.82 (2H, d,J=6.7 Hz), 2.09-2.05 (3H, m), 1.78 (2H, d, J=10.4 Hz), 1.34-1.23 (5H,m), 1.14-1.03 (2H, m). LC/MS: 440 [M+H].

Example 85:(4-((cis-4-(3-amino-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone(I-113)

Reductive amination of Compound I-36 with tert-butylN-(3-methylazetidin-3-yl)carbamate and subsequent isomer separation,followed by Boc deprotection provided Compound I-113. ¹H-NMR (DMSO-d₆)δ: 8.87 (1H, d, J=7.9 Hz), 8.21 (1H, s), 7.61-7.53 (3H, m), 7.49-7.44(2H, m), 4.23 (1H, s), 3.10 (2H, d, J=7.3 Hz), 3.30-2.80 (2H, br m),2.67 (2H, d, J=6.7 Hz), 2.11-2.09 (1H, m), 1.82-1.79 (2H, m), 1.67-1.41(6H, m), 1.27 (3H, s). LC/MS: 439 [M+H].

Example 86:(4-((trans-4-(3-amino-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone(I-114)

Reductive amination of Compound I-36 with tert-butylN-(3-methylazetidin-3-yl)carbamate and subsequent isomer separation,followed by Boc deprotection provided Compound I-114. ¹H-NMR (DMSO-d₆)δ: 8.70 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.59-7.54 (3H, m), 7.48-7.43(2H, m), 3.98-3.96 (1H, m), 3.11 (2H, d, J=7.3 Hz), 3.21-2.80 (2H, brm), 2.70 (2H, d, J=6.7 Hz), 2.11-1.99 (3H, m), 1.79-1.68 (2H, m),1.33-1.23 (5H, m), 1.12-1.03 (2H, m). LC/MS: 439 [M+H].

Example 87:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxy-2-methylpropanamide (I-115)

Acylation of Compound I-6 provided Compound I-115. ¹H-NMR (DMSO-d₆) δ:12.72 (1H, s), 8.96 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.62-7.53 (3H, m),7.50-7.46 (2H, m), 7.29 (1H, d, J=7.3 Hz), 5.45 (1H, s), 4.31-4.25 (1H,m), 3.73-3.65 (1H, m), 1.59-1.84 (8H, m), 1.23 (6H, s). LC/MS: 456[M+H].

Example 88:N—((S)-1-((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide(I-116)

N—((S)-1-((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide (I-116) was synthesizedaccording to General Procedure A, Step 2 via halogen displacement usingN-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide.¹H-NMR (DMSO-d₆) δ: 12.53 (1H, s), 8.60 (1H, d, J=7.3 Hz), 8.25 (1H, s),7.71 (1H, d, J=8.5 Hz), 7.61-7.54 (3H, m), 7.50-7.45 (2H, m), 4.25-4.10(2H, m), 3.94-3.83 (1H, m), 3.31-3.28 (1H, m), 3.14-3.08 (1H, m),2.20-2.16 (1H, m), 1.83 (3H, s), 1.70-1.42 (3H, m), 1.05 (3H, d, J=6.7Hz). LC/MS: 442 [M+H].

Example 89:N—((S)-1-((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide(I-117)

N—((S)-1-((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide (I-117) was synthesizedaccording to General Procedure A, Step 2 via halogen displacement usingN-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide.¹H-NMR (DMSO-d₆) δ: 8.75 (1H, d, J=6.7 Hz), 8.24 (1H, s), 7.70 (1H, d,J=9.2 Hz), 7.45-7.28 (5H, m), 4.23-4.13 (2H, m), 3.90-3.88 (1H, m),3.31-3.29 (1H, m), 3.12-3.10 (1H, m), 2.27 (3H, s), 2.20-2.17 (1H, m),1.84-1.82 (3H, m), 1.67-1.42 (3H, m), 1.05 (3H, d, J=6.7 Hz). LC/MS: 422[M+H].

Example 90:N-(((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide(I-118)

N-(((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide(I-118) was synthesized according to General Procedure A, Step 2 viahalogen displacement usingN-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide. ¹H-NMR(DMSO-d₆) δ: 12.75 (1H, s), 8.60 (1H, d, J=7.3 Hz), 8.26 (1H, s), 7.95(1H, t, J=5.8 Hz), 7.61-7.45 (5H, m), 4.16-4.13 (2H, m), 3.39-3.37 (1H,m), 3.21-3.05 (3H, m), 2.19-2.16 (1H, m), 1.83 (3H, s), 1.78-1.74 (1H,m), 1.60-1.57 (1H, m), 1.44-1.35 (1H, m). LC/MS: 428 [M+H].

Example 91:N-(((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide(I-119)

N-(((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide(I-119) was synthesized according to General Procedure A, Step 2 viahalogen displacement usingN-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide. ¹H-NMR(DMSO-d₆) δ: 8.75 (1H, d, J=6.7 Hz), 8.24 (1H, s), 7.95 (1H, t, J=5.8Hz), 7.45-7.28 (5H, m), 4.18-4.17 (2H, m), 3.21-3.05 (4H, m), 2.27 (3H,s), 2.19-2.16 (1H, m), 1.83 (3H, s), 1.77-1.74 (1H, m), 1.62-1.54 (1H,m), 1.42-1.36 (1H, m). LC/MS: 408 [M+H].

Example 92:N-(3-(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)methanesulfonamide(I-120) Step 1:(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitrophenyl)methanone(120a)

(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitrophenyl)methanone(120a) was synthesized according to General Procedure A, Step 1. ¹H-NMR(DMSO-D₆) δ: 13.45 (1H, s), 8.77 (1H, s), 8.56 (1H, s), 8.52 (1H, d,J=7.6 Hz), 8.33 (1H, s), 8.29 (1H, d, J=7.6 Hz), 7.86 (1H, t, J=7.6 Hz).

Step 2: tert-butylN-(cis-4-((5-(3-nitrobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cyclohexyl)-carbamate(120b)

tert-butylN-(cis-4-((5-(3-nitrobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cyclohexyl)-carbamate(120b) was synthesized according to General Procedure A, Step 2 viahalogen displacement using tert-butyl (cis-4-aminocyclohexyl)carbamate.LC/MS: 481 [M+H].

Step 3: tert-butylN-(cis-4-((5-(3-aminobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cyclohexyl)carbamate(120c)

Reduction of the nitro group using Palladium on Carbon (Pd/C) andammonium formate provided tert-butylN-(cis-4-((5-(3-aminobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cyclohexyl)carbamate(120c). LC/MS: 451 [M+H].

Step 4.N-(3-(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)methanesulfonamide(I-120)

Sulfonylation of 120c followed by a Boc deprotection of Boc providedCompound I-120. ¹H-NMR (DMSO-d₆) δ: 10.13 (1H, s), 8.40 (1H, s),8.16-7.98 (4H, m), 7.70-7.42 (3H, m), 4.29 (1H, br s), 3.25 (1H, br s),3.10 (3H, s), 2.33-2.23 (8H, m). LC/MS: 429 [M+H].

Example 93:N-(3-(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzenesulfonamide(I-121)

Phenylsulfonylation of tert-butylN-(cis-4-((5-(3-aminobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cyclohexyl)carbamatefollowed by Boc deprotection provided Compound I-121. ¹H-NMR (DMSO-d₆)δ: 10.74 (1H, s), 8.40 (1H, s), 8.15-8.02 (3H, br m), 7.86-7.40 (10H,m), 4.27 (1H, br s), 3.24 (1H, br s), 2.05-1.68 (8H, m). LC/MS: 491[M+H].

Example 93: Intermediate methyl 2-chloro-4-phenoxybenzoate (4-1)

To a stirred solution of methyl 2-chloro-4-fluorobenzoate (4-a, 7.35 g,39.0 mmol) and phenol (4-b, 4.40 g, 46.8 mmol) in DMF (100 mL) was addedCs₂CO₃ (19.0 g, 58.5 mmol) at room temperature. The reaction mixture wasstirred at 90° C. for 3 h and then extracted with Et₂O. The extract waswashed with water and brine, dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by column chromatography overSiO₂ with n-hexane-EtOAc to give methyl 2-chloro-4-phenoxybenzoate (4-1,9.58 g, 94%) as a colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ: 7.87 (1H, d,J=8.5 Hz), 7.43-7.39 (2H, m), 7.22 (1H, t, J=7.3 Hz), 7.07-7.05 (2H, m),7.01 (1H, d, J=2.4 Hz), 6.88 (1H, dd, J=8.5, 2.4 Hz), 3.91 (3H, s).LC/MS: 263 [M+H].

Example 94: IntermediateN-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-acetamidehydrochloride (5-1)

Step 1. tert-butylN-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)-ethyl)tetrahydro-2H-pyran-3-yl)carbamate(5-b)

To a stirred solution of tert-butyl N-((3R,6S)-6-((1R)-1-hydroxyethyl)tetrahydro-pyran-3-yl)carbamate (5-a, 9.96 g, 40.6 mmol), phthalimide(7.19 g, 48.7 mmol), and PPh₃ (12.77 g, 48.7 mmol) in THF (100 mL) wasadded dropwise diethyl azodicarboxylate (2.2 M in toluene, 22.1 mL, 48.7mmol) at 0° C. The resulting mixture was stirred for 3 h at roomtemperature and under reduced pressure. Addition of Et₂O to the mixturegave a precipitate which was removed by filtration. The filtrate wasconcentrated under reduced pressure and the resulting residue waspurified by column chromatography over SiO₂ eluting with n-hexane-EtOActo provide tert-butylN-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)tetrahydro-2H-pyran-3-yl)-carbamate(5-b, 13.82 g, 91%). ¹H-NMR (400 MHz, CDCl₃) δ: 7.87-7.77 (2H, m),7.72-7.68 (2H, m), 4.30-4.19 (2H, m), 3.92-3.87 (2H, m), 3.59-3.57 (1H,m), 2.88 (1H, t, J=10.4 Hz), 2.17-2.15 (1H, m), 1.94-1.91 (1H, m),1.46-1.29 (14H, m). LC/MS: 375 [M+H].

Step 2. tert-butylN-((3R,6S)-6-((1S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)carbamate (5-c)

The mixture of tert-butylN-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-tetrahydro-2H-pyran-3-yl)carbamate(5-b, 13.82 g, 36.9 mmol) and hydrazine monohydrate (5.4 mL, 110.7 mmol)in EtOH (200 mL) was stirred under reflux for 3 h and then cooled toroom temperature. After the resulting solid was removed by filtration,the filtrate was concentrated under reduced pressure. To the resultingresidue was added EtOAc and the resulting solid was again removed. Thiswas repeated until no precipitate came out of the solution.Concentration under reduced pressure provided tert-butylN-((3R,6S)-6-((1S)-1-amino-ethyl)tetrahydro-2H-pyran-3-yl)carbamate(5-c, 7.54 g, 83%) which was used in the next step without furtherpurification. LC/MS: 245 [M+H].

Step 3. tert-butylN-((3R,6S)-6-((1S)-1-acetamidoethyl)-tetrahydro-pyran-3-yl)carbamate(5-d)

To a stirred solution of tert-butylN-((3R,6S)-6-((1S)-1-aminoethyl)-tetrahydro-2H-pyran-3-yl)-carbamate(5-c, 7.54 g, 30.9 mmol) and Et₃N (8.6 mL, 61.7 mL) in DMF (30 mL) wasadded acetic anhydride (Ac₂O, 4.3 mL, 46.3 mL) at room temperature.After stirring for 1 h at room temperature, the reaction mixture wasquenched with saturated aqueous NaHCO₃ and then concentration in vacuo.The resulting residue was extracted with CH₂Cl₂, washed with H₂O, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by column chromatography over SiO₂ andeluting with n-hexane-EtOAc to provide tert-butylN-((3R,6S)-6-((1S)-1-acetamidoethyl)-tetrahydro-pyran-3-yl)carbamate(5-d) which was used in the next step without further purification.¹H-NMR (CDCl₃) δ: 5.77-5.74 (1H, m), 4.28 (1H, d, J=7.9 Hz), 4.10-4.07(1H, m), 4.03-3.96 (1H, m), 3.61-3.52 (1H, m), 3.19 (1H, d, J=11.0 Hz),2.98-2.96 (1H, m), 2.08-2.06 (1H, m), 1.99 (3H, s), 1.64-1.24 (12H, m),1.18 (3H, d, J=6.7 Hz). LC/MS: 287 [M+H].

Step 4.N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-acetamidehydrochloride (5-1)

To a stirred solution of tert-butylN-((3R,6S)-6-((1S)-1-acetamidoethyl)-tetra-hydro-2H-pyran-3-yl)carbamate(5-d, 30.9 mmol) in DCM (40 mL) was added 4 N HCl in dioxane (40 mL) atroom temperature and the reaction mixture was stirred at roomtemperature for 1 h. The resulting mixture was concentrated in vacuo.The resulting solid was washed with EtOAc under sonication and thencollected by filtration to giveN-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamidehydrochloride (5-1, 6.87 g, over 2 steps) as a colorless solid. LC/MS:187 [M+H].

Example 95:N—((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide(I-122)

Step 1.(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo-[2,3-d]pyrimidin-5-yl)methanone(122a)

To a stirred solution of 3-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine(3-A, 6.90 g, 29.7 mmol) in THF (200 mL) was added dropwise n-BuLi (2.69M in hexane, 23.2 mL, 62.3 mmol) at −78° C. under an atmosphere ofnitrogen (N₂). The reaction mixture was stirred at −78° C. for 50 minand methyl 2-chloro-4-phenoxybenzoate (4-1, 8.19 g, 31.2 mmol) was thenadded at the same temperature. After stirring at −78° C. for 50 min, thereaction mixture was quenched with 1 N HCl (65 mL), warmed to roomtemperature, and extracted with EtOAc. The extract was washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resulting residue was purified by column chromatographyover SiO₂ eluting with n-hexane-EtOAc to give(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(122a, 4.73 g, 41%) as a colorless solid. ¹H-NMR (400 MHz,CDCl₃/CD₃OD=9/1) δ: 8.69 (1H, d, J=1.8 Hz), 7.71 (1H, d, J=1.8 Hz), 7.50(1H, dd, J=8.5, 1.8 Hz), 7.46-7.41 (2H, m), 7.27-7.21 (1H, m), 7.13-7.09(2H, m), 7.07-7.05 (1H, m), 6.96-6.93 (1H, m), 3.40 (1H, br s). LC/MS:386 [M+H, ³⁵Cl+³⁵Cl], 384 [M+H, ³⁵Cl+³⁷Cl].

Step 2.N—((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide(I-122)

The mixture of(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone(122a, 1.0 g, 2.60 mmol),N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamidehydrochloride (5-1, 638 mg, 2.86 mmol), and DIPEA (1.359 mL, 7.80 mmol)in IPA (10 mL) was stirred at 160° C. for 1 h under microwaveirradiation and the resulting mixture was concentrated under reducedpressure. The resulting residue was purified by column chromatographyover NH₂—SiO₂ eluting with CH₂Cl₂-MeOH to giveN—((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide(I-122, 638 mg, 2.86 mmol) as a colorless solid. ¹H-NMR (DMSO-d₆) δ:12.76 (1H, s), 8.58 (1H, d, J=7.3 Hz), 8.25 (1H, s), 7.70 (1H, d, J=8.5Hz), 7.64 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.49-7.47 (2H, m), 7.27-7.25(1H, m), 7.19-7.18 (3H, m), 7.03-7.01 (1H, m), 4.21-4.14 (2H, m),3.90-3.88 (1H, m), 3.31-3.30 (1H, m), 3.12-3.09 (1H, m), 2.19-2.16 (1H,m), 1.83 (3H, s), 1.68-1.42 (3H, m), 1.05 (3H, d, J=6.7 Hz). LC/MS: 536[M+H, ³⁷Cl], 534 [M+H, ³⁵Cl].

Example 96:(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-123)

The mixture of(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)methanone(122a, 200 mg, 0.52 mmol),((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)-methanol (123a, 72 mg, 0.54mmol), and DIPEA (272 μL, 1.56 mmol) in IPA (4 mL) was stirred at 160°C. for 1 h under microwave irradiation and then concentrated underreduced pressure. The resulting residue was purified by columnchromatography over NH₂—SiO₂ eluting with CH₂Cl₂-MeOH to give(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-123, 175 mg, 70%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ:12.75 (1H, brs), 8.60 (1H, d, J=6.7 Hz), 8.25 (1H, d, J=1.8 Hz), 7.64(1H, d, J=1.8 Hz), 7.49-7.48 (2H, m), 7.27-7.25 (1H, m), 7.20-7.18 (3H,m), 7.04-7.01 (1H, m), 4.68-4.67 (1H, m), 4.17-4.15 (2H, m), 3.43-3.32(3H, m), 3.14-3.11 (1H, m), 2.21-2.18 (1H, m), 1.80-1.77 (1H, m),1.58-1.55 (1H, m), 1.41-1.38 (1H, m). LC/MS: 481 [M+H, ³⁷Cl], 479 [M+H,³⁵Cl].

Example 97:Intermediate-N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamidehydrochloride (6-1)

Step 1. tert-butylN-((3R,6S)-6-((1,3-dioxoisoindolin-2-yl)methyl)-tetrahydro-2H-pyran-3-yl)carbamate(6-b)

tert-butylN-((3R,6S)-6-((1,3-dioxoisoindolin-2-yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate(6-b, 2.5 g, 81%) was synthesized according to the procedure describedabove for

Step 1 in Example 94 from tert-butylN-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (6-a, 2.0g, 8.6 mmol). LC/MS: 305 [M-tBu+2H] Step 2. tert-butylN-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (6-c)

tert-butyl N-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate(6-c, 1.6 g, quantitative) was synthesized according to the proceduredescribed above for Step 2 in Example 94 from tert-butylN-((3R,6S)-6-((1,3-dioxo-isoindolin-2-yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate(6-b, 2.5 g, 7.0 mmol). LC/MS: 231 [M+H].

Step 3. tert-butylN-((3R,6S)-6-(acetamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (6-d)

tert-butylN-((3R,6S)-6-(acetamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (845mg, 44%) was synthesized according to the procedure described above forStep 3 in Example 94 from tert-butylN-((3R,6S)-6-(aminomethyl)-tetrahydro-2H-pyran-3-yl)carbamate (1.6 g,7.0 mmol). ¹H-NMR (CDCl₃) δ: 5.90 (1H, br s), 4.26 (1H, br s), 4.08-4.06(1H, m), 3.61-3.58 (2H, m), 3.33-3.31 (1H, m), 3.01-2.98 (2H, m),2.08-2.05 (1H, m), 1.99 (3H, s), 1.44-1.19 (13H, m). LC/MS: 273 [M+H].

Step 4. N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamidehydrochloride (6-1)

N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamidehydrochloride (607 mg, 98%) was synthesized according to the proceduredescribed above for Step 4 in Example 94 from tert-butylN-((3R,6S)-6-(acetamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (845mg, 3.1 mmol). ¹H-NMR (DMSO-d₆) δ: 8.30 (3H, br s), 8.00 (1H, t, J=5.5Hz), 4.03-4.00 (1H, m), 3.28-3.24 (2H, m), 3.13-2.99 (3H, m), 2.08-2.05(1H, m), 1.82-1.78 (3H, m), 1.70-1.66 (1H, m), 1.57-1.51 (1H, m),1.26-1.17 (1H, m). LC/MS: 173 [M+H].

Example 98:N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide(I-127)

N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide(I-127, 88 mg, 61%) was synthesized according to the procedure describedherein above for Example 96 fromN-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamidehydrochloride (6-1, 100 mg, 0.26 mmol). ¹H-NMR (DMSO-d₆) δ: 12.63 (1H,br s), 8.59 (1H, d, J=6.7 Hz), 8.26 (1H, s), 7.95 (1H, t, J=5.8 Hz),7.64 (1H, s), 7.58 (1H, d, J=8.5 Hz), 7.51-7.45 (2H, m), 7.27-7.25 (1H,m), 7.19-7.18 (3H, m), 7.02 (1H, dd, J=8.5, 2.4 Hz), 4.20-4.10 (2H, m),3.22-3.04 (4H, m), 2.21-2.12 (1H, m), 1.85-1.73 (4H, m), 1.64-1.50 (1H,m), 1.45-1.33 (1H, m). LC/MS: 522 [M+H, ³⁷Cl], 520 [M+H, ³⁵Cl].

Example 99: General Procedure B

Step 1. Intermediate 3-C

To a stirred solution of 3-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine(3-A) in THF was added n-BuLi solution (in hexane, 2-3 eq.) dropwise at−78° C. and under inert atmosphere. The reaction mixture was stirred at−78° C. for 0.5-2 hrs and an ester or acid chloride (3-B, 1-2 eq.) wasthen added at −78° C. After stirring at −78° C. for 0.5-2 hrs, thereaction mixture was quenched with 1 N HCl aqueous. Work-up and/orpurification provided the corresponding aryl- orheteroaryl-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (3-C).

Step 2. Compounds of Formula I-Y

A mixture of 3-C, a primary amine (3-D, 1-4 eq.), and optionally a base(e.g., TEA, DIPEA, pyridine, and/or K₂CO₃ (1-5 eq.)) in a solvent (e.g.,DMF, NMP, IPA, n-BuOH or neat) was heated (70-160° C.) for 5-50 hrs orheated (100-220° C.) under microwave radiation for 0.5-5 hrs. Work-upand/or purification provided a compound of Formula (I) (aryl- orheteroaryl-[4-(substituted-amino)]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone(I-Y)).

The compounds of Formula (I) in Table 2 below were made according toGeneral Procedure B using the applicable aryl or heteroaryl ester oracid chloride and amine.

TABLE 2 Cmpd No. ¹H NMR and/or LC/MS data I-124 ¹H NMR (300 MHz,DMSO-d₆) δ: 12.71 (1H, brs), 8.57 (1H, d, J = 6.9 Hz), 8.23 (1H, s,),7.61 (1H, s), 7.55 (1H, d, J = 8.4 Hz), 7.46 (2H, t, J = 8.0 Hz),7.30-7.00 (4H, m), 6.99 (1H, dd, J = 8.7, 2.1 Hz), 4.70-4.60 (1H, m),4.20-3.90 (2H, m), 3.45-3.30 (1H, m), 3.10 (1H, t, J = 11.6 Hz), 2.16(1H, d, J = 10.5 Hz), 1.76 (1H, d, J = 12.6 Hz), 1.65-1.45 (1H, m),1.45-1.25 (1H, m), 1.20-1.05 (1H, m), 1.05-0.90 (1H, m). LC/MS: 481 [M +H, ³⁷Cl], 479 [M + H, ³⁵Cl]. I-125 ¹H NMR (300 MHz, DMSO-d₆) δ: 12.63(1H, br s), 9.19 (1H, d, J = 8.1 Hz), 8.20 (1H, s), 7.60-7.55 (2H, m),7.46 (2H, t, J = 8.0 Hz), 7.26-7.10 (4H, m), 7.01 (1H, dd, J = 8.7, 2.4Hz), 4.65-4.60 (1H, m), 4.35-4.25 (1H, m), 4.05-3.85 (1H, m), 3.62 (1H,d, J = 10.5 Hz), 3.60-3.25 (3H, m), 1.95-1.80 (2H, m), 1.65-1.50 (2H,m). LC/MS: 481 [M + H, ³⁷Cl], 479 [M + H, ³⁵Cl]. I-126 ¹H NMR (300 MHz,DMSO-d₆) δ: 12.69 (1H, br s), 9.19 (1H, d, J = 7.8 Hz), 8.21 (1H, s),7.62-7.54 (2H, m), 7.46 (2H, t, J = 8.0 Hz), 7.26-7.01 (4H, m), 7.01(1H, dd, J = 8.4, 2.4 Hz), 4.64-4.60 (1H, m), 4.31 (1H, d, J = 7.5 Hz),3.91 (1H, d, J = 11.7 Hz), 3.62 (1H, d, J = 10.2 Hz), 3.47-3.25 (3H, m),2.01-1.75 (2H, m), 1.65-1.45 (2H, m). LC/MS: 481 [M + H, ³⁷Cl], 479 [M +H, ³⁵Cl]. I-129 ¹H-NMR (DMSO-d₆) δ: 12.61 (1H, s), 8.89 (0.65H, d, J =7.9 Hz), 8.43 (0.35H, d, J = 7.3 Hz), 8.20 (0.65H, s), 8.21 (0.35H, s),7.98 (0.35H, s), 8.01 (0.65H, s), 7.82-7.84 (1H, m), 7.14-7.15 (1H, m),4.38-4.39 (0.65H, m), 3.96-4.00 (0.35H, m), 2.43 (1.05H, s), 2.45(1.95H, s), 2.06-2.09 (0.65H, m), 1.03-1.81 (8.35H, m), 0.84-0.95 (3H,m). LC/MS: 355 [M + H]. (diastereo mixture: 65/35) I-130 ¹H-NMR(DMSO-d₆) δ: 8.36 (1H, s), 8.06-8.01 (4H, m), 7.89 (2H, d, J = 7.9 Hz),7.49 (2H, t, J = 7.6 Hz), 7.27 (1H, t, J = 7.0 Hz), 7.17 (2H, d, J = 7.9Hz), 7.12 (2H, d, J = 7.9 Hz), 4.27-4.23 (1H, m), 3.24-3.18 (1H, m),2.00-1.71 (8H, m). LC/MS: 428 [M + H]. I-131 ¹H-NMR (DMSO-d₆) δ: 8.37(1H, s), 8.10-8.02 (4H, m), 7.60-7.58 (2H, m), 7.47-7.43 (2H, m),7.35-7.32 (2H, m), 7.21 (1H, t, J = 7.3 Hz), 7.13 (2H, d, J = 7.9 Hz),4.27-4.25 (1H, m), 3.23-3.20 (1H, m), 1.98-1.69 (8H, m). LC/MS: 428 [M +H]. I-133 ¹H-NMR (DMSO-d₆) δ: 12.62 (1H, s), 8.95 (1H, d, J = 7.3 Hz),8.21 (1H, s), 7.76 (1H, s), 7.46 (1H, t, J = 7.9 Hz), 7.36 (1H, d, J =7.9 Hz), 7.29 (1H, s), 7.21 (1H, d, J = 7.3 Hz), 6.96-6.93 (1H, m),4.23-4.19 (1H, m), 3.83 (3H, s), 3.45-3.37 (1H, m), 1.88-1.80 (2H, m),1.73-1.59 (6H, m), 1.38 (9H, s). LC/MS: 466 [M + H]. I-134 ¹H-NMR(DMSO-d₆) δ: 12.57 (1H, s), 9.03 (1H, d, J = 7.3 Hz), 8.21 (1H, s), 7.41(1H, s), 7.24 (1H, d, J = 8.5 Hz), 7.01-6.95 (3H, m), 4.24-4.20 (1H, m),3.76 (3H, s), 3.44-3.40 (1H, m), 2.19 (3H, s), 1.86-1.79 (2H, m),1.74-1.59 (6H, m), 1.38 (9H, s). LC/MS: 480 [M + H]. I-142 ¹H-NMR(DMSO-d₆) δ: 12.67 (1H, s), 8.65 (1H, d, J = 7.3 Hz), 8.23 (1H, s),7.85-7.80 (3H, m), 7.50-7.46 (2H, m), 7.25 (1H, t, J = 7.3 Hz),7.17-7.14 (2H, m), 7.10-7.07 (2H, m), 4.59 (1H, d, J = 5.5 Hz),4.17-4.12 (2H, m), 3.53-3.45 (1H, m), 3.11-3.04 (2H, m), 2.20-2.16 (1H,m), 1.94-1.89 (1H, m), 1.57-1.35 (2H, m), 1.08 (3H, d, J = 6.1 Hz).LC/MS: 459 [M + H]. I-146 ¹H-NMR (DMSO-d₆) δ: 12.67 (1H, br s), 8.66(1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.86-7.80 (3H, m), 7.51-7.45 (2H, m),7.28-7.23 (1H, m), 7.18-7.14 (2H, m), 7.11-7.06 (2H, m), 4.66 (1H, t, J= 5.8 Hz), 4.18-4.09 (2H, m), 3.45-3.35 (2H, m), 3.10 (1H, t, J = 11.3Hz), 2.20-2.13 (1H, m), 1.81-1.74 (1H, m), 1.62-1.50 (1H, m), 1.44-1.31(1H, m). LC/MS: 445 [M + H]. I-147 ¹H-NMR (CDCl₃) δ: 8.80 (1H, d, J =7.3 Hz), 8.37 (1H, s), 7.80 (2H, d, J = 8.5 Hz), 7.58 (1H, s), 7.42 (2H,t, J = 8.2 Hz), 7.25-7.19 (1H, m), 7.13-7.06 (4H, m), 4.42-4.28 (2H, m),3.27 (1H, t, J = 10.4 Hz), 3.21-3.15 (1H, m), 2.55 (1H, br s), 2.38-2.31(1H, m), 1.84-1.51 (4H, m), 1.21 (6H, d, J = 10.4 Hz). LC/MS: 473 [M +H]. I-149 ¹H-NMR (DMSO-d₆) δ: 12.70 (1H, s), 8.65 (1H, d, J = 7.3 Hz),8.50 (1H, d, J = 3.1 Hz), 8.48-8.46 (1H, m), 8.24 (1H, s), 7.87-7.82(3H, m), 7.64-7.61 (1H, m), 7.51 (1H, dd, J = 8.2, 4.6 Hz), 7.16 (2H, d,J = 8.5 Hz), 4.60 (1H, d, J = 4.9 Hz), 4.17-4.11 (2H, m), 3.52-3.46 (1H,m), 3.11-3.04 (2H, m), 2.20-2.15 (1H, m), 1.94-1.90 (1H, m), 1.58-1.48(1H, m), 1.45-1.35 (1H, m), 1.08 (3H, d, J = 6.7 Hz). LC/MS: 460 [M +H]. I-150 ¹H-NMR (DMSO-d₆) δ: 12.76 (1H, s), 8.58 (1H, d, J = 7.3 Hz),8.25 (1H, s), 7.64 (1H, s), 7.58 (1H, d, J = 8.5 Hz), 7.51-7.46 (2H, m),7.28-7.24 (1H, m), 7.20-7.17 (3H, m), 7.02 (1H, dd, J = 8.2, 2.1 Hz),4.60 (1H, d, J = 5.5 Hz), 4.19-4.10 (2H, m), 3.51-3.46 (1H, m),3.13-3.06 (2H, m), 2.22-2.17 (1H, m), 1.95-1.90 (1H, m), 1.59-1.50 (1H,m), 1.46-1.36 (1H, m), 1.08 (3H, d, J = 6.7 Hz). LC/MS: 493 [M + H].I-151 ¹H-NMR (DMSO-d₆) δ: 12.72 (1H, s), 8.92 (1H, d, J = 7.3 Hz), 8.23(1H, s), 7.90 (1H, d, J = 7.3 Hz), 7.62 (1H, s), 7.59 (1H, d, J = 8.5Hz), 7.51-7.46 (2H, m), 7.28-7.24 (1H, m), 7.20-7.17 (3H, m), 7.03 (1H,dd, J = 8.2, 2.1 Hz), 4.26-4.22 (1H, m), 3.75-3.70 (1H, m), 1.81 (3H,s), 1.84-1.57 (8H, m). LC/MS: 504 [M + H]. I-152 ¹H-NMR (DMSO-d₆) δ:12.64 (1H, s), 8.97 (1H, d, J = 6.7 Hz), 8.22 (1H, s), 7.88-7.83 (3H,m), 7.78 (1H, s), 7.34-7.29 (2H, m), 7.24-7.20 (2H, m), 7.10-7.06 (2H,m), 4.23-4.20 (1H, m), 3.73-3.69 (1H, m), 1.85-1.57 (8H, m), 1.80 (3H,s). LC/MS: 488 [M + H]. I-153 ¹H-NMR (DMSO-d₆) δ: 12.66 (1H, s), 8.98(1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.90-7.86 (3H, m), 7.81 (1H, s), 7.70(1H, t, J = 7.9 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.50 (1H, s), 7.47-7.44(1H, m), 7.21-7.17 (2H, m), 4.24-4.20 (1H, m), 3.74-3.69 (1H, m), 1.80(3H, s), 1.87-1.55 (8H, m). LC/MS: 538 [M + H]. I-155 ¹H-NMR (DMSO-d₆)δ: 12.67 (1H, s), 8.93 (1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.86-7.84 (2H,m), 7.82-7.80 (1H, m), 7.49-7.46 (2H, m), 7.27-7.23 (1H, m), 7.17-7.14(2H, m), 7.10-7.08 (2H, m), 4.24-4.21 (1H, m), 3.89-3.87 (1H, m),3.69-3.64 (1H, m), 3.59-3.54 (1H, m), 3.42-3.38 (1H, m), 2.05-1.99 (1H,m), 1.83-1.81 (1H, m), 1.74-1.56 (2H, m). LC/MS: 415 [M + H]. I-156¹H-NMR (DMSO-d₆) δ: 12.67 (1H, s), 8.88 (1H, d, J = 7.3 Hz), 8.24 (1H,s), 7.87-7.84 (2H, m), 7.81 (1H, s), 7.51-7.45 (2H, m), 7.27-7.24 (1H,m), 7.17-7.14 (2H, m), 7.10-7.08 (2H, m), 4.30-4.27 (1H, m), 3.91-3.89(2H, m), 3.54-3.48 (2H, m), 2.02-2.00 (2H, m), 1.56-1.51 (2H, m). LC/MS:415 [M + H]. I-157 ¹H-NMR (CDCl₃) δ: 13.03 (1H, br s), 8.94 (1H, d, J =7.3 Hz), 8.38 (1H, s), 7.80 (2H, d, J = 8.5 Hz), 7.64 (1H, s), 7.46-7.39(2H, m), 7.22 (1H, t, J = 7.3 Hz), 7.10 (4H, t, J = 9.2 Hz), 6.61 (1H,d, J = 3.1 Hz), 5.91 (1H, d, J = 3.1 Hz), 4.45-4.34 (2H, m), 3.93-3.87(1H, m), 3.33 (1H, t, J = 10.4 Hz), 2.42-2.30 (2H, m), 1.85-1.64 (2H,m). LC/MS: 458 [M + H]. I-158 ¹H-NMR (DMSO-d₆) δ: 12.66 (1H, s), 9.16(1H, s), 8.83 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.87-7.84 (2H, m), 7.81(1H, s), 7.50-7.46 (2H, m), 7.27-7.24 (1H, m), 7.17-7.16 (2H, m),7.10-7.08 (2H, m), 4.12-4.07 (1H, m), 3.13-3.07 (1H, m), 2.23-2.16 (4H,m), 1.74-1.68 (2H, m), 1.54-1.47 (2H, m). LC/MS: 481 [M + H]. I-159¹H-NMR (DMSO-d₆) δ: 12.13 (1H, s), 8.83 (1H, d, J = 7.3 Hz), 8.24 (1H,s), 7.86-7.84 (2H, m), 7.82-7.79 (1H, m), 7.50-7.46 (2H, m), 7.27-7.25(1H, m), 7.17-7.15 (2H, m), 7.10-7.08 (2H, m), 4.13-4.05 (1H, m), 3.34(3H, s), 3.01 (1H, s), 2.20-2.14 (4H, m), 1.75-1.66 (2H, m), 1.54-1.45(2H, m). LC/MS: 495 [M + H]. I-160 ¹H-NMR (CDCl₃) δ: 13.32 (1H, br s),8.89 (1H, d, J = 7.3 Hz), 8.36 (1H, s), 7.83-7.78 (2H, m), 7.64 (1H, s),7.45-7.39 (2H, m), 7.22 (1H, t, J = 7.3 Hz), 7.13-7.06 (4H, m),4.41-4.29 (2H, m), 3.70-3.63 (1H, m), 3.30-3.21 (1H, m), 3.18-3.11 (1H,m), 2.37-2.29 (1H, m), 1.84-1.65 (3H, m), 1.61-1.49 (1H, m), 1.19 (3H,d, J = 6.7 Hz). LCMS: 459 [M + H]. I-161 ¹H-NMR (DMSO-d₆) δ: 12.65 (1H,s), 8.97 (1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.88-7.85 (3H, m), 7.79 (1H,s), 7.53-7.50 (2H, m), 7.19-7.18 (2H, m), 7.14-7.13 (2H, m), 4.23-4.20(1H, m), 3.72-3.70 (1H, m), 1.88-1.55 (11H, m). LC/MS: 504 [M + H].(Synthesized from [4-(4-chlorophenoxy)phenyl]-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone, LC/MS: 384 [M + H].) I-162 ¹H-NMR (DMSO-d₆)δ: 12.63 (1H, s), 8.97 (1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.88-7.82 (3H,m), 7.78 (1H, s), 7.28 (2H, d, J = 8.5 Hz), 7.05 (4H, d, J = 8.5 Hz),4.22-4.19 (1H, m), 3.72-3.70 (1H, m), 2.33 (3H, s), 1.87-1.53 (11H, m).LC/MS: 484 [M + H]. (Synthesized from(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-(4-methylphenoxy)phenyl)methanone LC/MS: 364 [M + H]) I-163 ¹H-NMR(DMSO-d₆) δ: 12.58 (1H, s), 8.98 (1H, d, J = 6.7 Hz), 8.21 (1H, s), 7.87(1H, d, J = 7.3 Hz), 7.79-7.77 (3H, m), 7.09 (2H, d, J = 9.2 Hz),6.01-5.97 (1H, m), 5.87-5.85 (1H, m), 5.05-5.02 (1H, m), 4.22-4.20 (1H,m), 3.72-3.71 (1H, m), 2.13-1.91 (3H, m), 1.80-1.57 (14H, m). LC/MS: 474[M + H]. (Synthesized from methyl 4- hydroxybenzoate and3-bromocyclohexene LC/MS: 233 [M + H] and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-cyclohex-2-en-1-yloxyphenyl)methanoneLC/MS: 354 [M + H].) I-164 ¹H-NMR (DMSO-d₆) δ: 12.78 (1H, s), 8.82 (1H,d, J = 7.3 Hz), 8.24 (1H, s), 8.10 (1H, d, J = 7.9 Hz), 7.90 (1H, d, J =7.3 Hz), 7.82 (1H, s), 7.50-7.48 (2H, m), 7.31-7.26 (3H, m), 7.11 (1H,d, J = 7.9 Hz), 4.24-4.21 (1H, m), 3.74-3.71 (1H, m), 1.81-1.58 (11H,m). LC/MS: 505 [M + H]. (Synthesized from (2-chloro-6-phenoxy-3-pyridyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone LC/MS: 385[M + H].) I-165 ¹H-NMR (CDCl₃) δ: 8.98 (1H, d, J = 7.9 Hz), 8.34 (1H,s), 7.81 (2H, d, J = 8.8 Hz), 7.59 (1H, s), 7.42 (2H, t, J = 7.9 Hz),7.24-7.19 (1H, m), 7.13-7.06 (4H, m), 4.19-4.07 (1H, m), 3.52 (2H, d, J= 6.1 Hz), 2.30-2.23 (2H, m), 1.96-1.38 (6H, m), 1.27-1.15 (2H, m).LC/MS: 443 [M + H]. I-168 ¹H-NMR (DMSO-d₆) δ: 12.62 (1H, s), 8.75 (1H,d, J = 7.3 Hz), 8.22 (1H, s), 7.85-7.81 (2H, m), 7.78 (1H, s), 7.50-7.46(2H, m), 7.25 (1H, t, J = 7.3 Hz), 7.16 (2H, d, J = 7.9 Hz), 7.10-7.06(2H, m), 4.60 (1H, d, J = 4.3 Hz), 4.02-3.97 (1H, m), 3.54-3.50 (1H, m),2.09-2.03 (2H, m), 1.89-1.85 (2H, m), 1.38-1.29 (4H, m). LC/MS: 429 [M +H]. I-169 ¹H-NMR (DMSO-d₆) δ: 12.70 (1H, s), 8.69 (1H, d, J = 7.9 Hz),8.23 (1H, s), 7.60-7.58 (1H, m), 7.57 (1H, d, J = 7.3 Hz), 7.50-7.46(2H, m), 7.26 (1H, t, J = 7.6 Hz), 7.20-7.17 (3H, m), 7.02 (1H, dd, J =8.2, 2.1 Hz), 4.60 (1H, d, J = 4.3 Hz), 4.03-3.98 (1H, m), 3.55-3.49(1H, m), 2.10-2.05 (2H, m), 1.90-1.85 (2H, m), 1.40-1.28 (4H, m). LC/MS:463 [M + H]. I-171 ¹H-NMR (DMSO-d₆) δ: 12.70 (1H, s), 8.67 (1H, d, J =6.7 Hz), 8.24-8.22 (1H, m), 8.24 (1H, s), 7.95-7.91 (1H, m), 7.88-7.83(3H, m), 7.27 (2H, d, J = 7.9 Hz), 7.24-7.20 (1H, m), 7.15 (1H, d, J =7.9 Hz), 4.60 (1H, d, J = 5.5 Hz), 4.18-4.12 (2H, m), 3.52-3.47 (1H, m),3.12-3.05 (2H, m), 2.21-2.16 (1H, m), 1.95-1.90 (1H, m), 1.59-1.49 (1H,m), 1.46-1.36 (1H, m), 1.08 (3H, d, J = 5.5 Hz). LC/MS: 460 [M + H].I-172 ¹H-NMR (DMSO-d₆) δ: 12.71 (1H, s), 8.66 (1H, d, J = 7.3 Hz), 8.24(1H, s), 7.98 (1H, t, J = 7.9 Hz), 7.91-7.84 (3H, m), 7.35-7.31 (3H, m),7.15 (1H, d, J = 7.9 Hz), 4.60 (1H, d, J = 5.5 Hz), 4.18-4.12 (2H, m),3.52-3.47 (1H, m), 3.12-3.05 (2H, m), 2.21-2.16 (1H, m), 1.95-1.90 (1H,m), 1.59-1.49 (1H, m), 1.46-1.36 (1H, m), 1.08 (3H, d, J = 6.1 Hz).LC/MS: 494 [M + H]. I-173 ¹H-NMR (DMSO-d₆) δ: 12.77 (1H, s), 8.92 (1H,d, J = 6.7 Hz), 8.27 (1H, s), 7.65 (1H, s), 7.58 (1H, d, J = 8.5 Hz),7.50-7.46 (2H, m), 7.28-7.24 (1H, m), 7.20-7.17 (3H, m), 7.03 (1H, dd, J= 8.2, 2.1 Hz), 4.73-4.66 (1H, m), 3.96-3.90 (2H, m), 3.83-3.76 (1H, m),3.68 (1H, dd, J = 8.9, 3.4 Hz), 2.39-2.30 (1H, m), 1.94-1.85 (1H, m).LC/MS: 435 [M + H]. I-174 ¹H-NMR (DMSO-d₆) δ: 12.77 (1H, s), 8.92 (1H,d, J = 6.7 Hz), 8.27 (1H, s), 7.65 (1H, s), 7.58 (1H, d, J = 8.5 Hz),7.51-7.45 (2H, m), 7.26 (1H, t, J = 7.6 Hz), 7.20-7.17 (3H, m), 7.02(1H, dd, J = 8.5, 2.4 Hz), 4.73-4.66 (1H, m), 3.96-3.90 (2H, m),3.82-3.76 (1H, m), 3.66-3.70 (1H, m), 2.39-2.30 (1H, m), 1.93-1.86 (1H,m). LC/MS: 435 [M + H]. I-179 ¹H-NMR (DMSO-d₆) δ: 12.71 (1H, s), 8.71(1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.60-7.58 (2H, m), 7.49-7.47 (2H, m),7.27-7.25 (1H, m), 7.20-7.18 (3H, m), 7.02 (1H, dd, J = 8.5, 2.4 Hz),4.55 (1H, d, J = 5.5 Hz), 4.35 (1H, d, J = 3.1 Hz), 4.13-4.00 (1H, m),3.76-3.74 (1H, m), 3.54-3.52 (1H, m), 3.17 (3H, d, J = 5.5 Hz),1.95-1.92 (1H, m), 1.78-1.74 (2H, m). LC/MS: 479 [M + H]. Racemicmixture. I-180 ¹H-NMR (DMSO-d₆) δ: 12.71 (1H, s), 8.71 (1H, d, J = 7.9Hz), 8.23 (1H, s), 7.59-7.56 (2H, m), 7.50-7.46 (2H, m), 7.26-7.25 (1H,m), 7.19-7.18 (3H, m), 7.02 (1H, dd, J = 8.5, 2.4 Hz), 4.43-4.40 (3H,m), 3.84-3.83 (1H, m), 3.60-3.59 (1H, m), 2.04-2.01 (2H, m), 1.73-1.57(3H, m), 1.35-1.33 (1H, m). LC/MS: 479 [M + H]. Racemic mixture. I-184¹H-NMR (CDCl₃) δ: 9.14 (1H, d, J = 7.3 Hz), 8.36 (1H, s), 7.82-7.78 (2H,m), 7.60 (1H, s), 7.45-7.39 (2H, m), 7.24-7.18 (1H, m), 7.13-7.06 (4H,m), 4.74-4.60 (2H, m), 4.21 (1H, br s), 2.39-2.24 (2H, m), 2.18-1.99(2H, m), 1.79-1.67 (1H, m), 1.62-1.47 (1H, m), 1.45 (9H, s). LC/MS: 514[M + H]. I-185 ¹H-NMR (CDCl₃) δ: 9.34 (1H, d, J = 5.5 Hz), 8.36 (1H, s),7.81 (2H, d, J = 8.5 Hz), 7.62 (1H, s), 7.42 (2H, t, J = 7.9 Hz), 7.21(1H, t, J = 7.3 Hz), 7.13-7.06 (4H, m), 4.92 (1H, br s), 4.81-4.71 (1H,m), 4.33 (1H, br s), 2.62-2.38 (4H, m), 1.45 (9H, s). LC/MS: 500 [M +H]. I-186 ¹H-NMR (CDCl₃) δ: 9.19 (1H, d, J = 7.3 Hz), 8.36 (1H, s), 7.81(2H, d, J = 8.5 Hz), 7.62 (1H, s), 7.45-7.40 (2H, m), 7.22 (1H, t, J =7.3 Hz), 7.14-7.06 (4H, m), 4.76 (1H, d, J = 6.7 Hz), 4.53-4.40 (1H, m),4.06-3.93 (1H, m), 3.05-2.93 (2H, m), 2.03-1.91 (2H, m), 1.45 (9H, s).LC/MS: 500 [M + H]. I-187 ¹H-NMR (CDCl₃) δ: 12.64 (1H, s), 9.01 (1H, d,J = 7.3 Hz), 8.21 (1H, s), 7.85 (2H, dt, J = 9.2, 2.3 Hz), 7.80 (1H, s),7.51-7.45 (2H, m), 7.28-7.23 (1H, m), 7.19-7.15 (2H, m), 7.12-7.07 (2H,m), 4.69-4.62 (2H, m), 3.51 (2H, dd, J = 6.7, 5.5 Hz), 2.41-2.21 (3H,m), 2.07-1.98 (2H, m). LC/MS: 415 [M + H]. I-188 ¹H-NMR (DMSO-d₆) δ:12.78 (1H, s), 8.58 (1H, d, J = 7.3 Hz), 8.25 (1H, s), 7.64 (1H, s),7.58 (1H, d, J = 8.5 Hz), 7.49-7.47 (2H, m), 7.27-7.25 (1H, m),7.19-7.18 (3H, m), 7.03-7.01 (1H, m), 4.29 (1H, s), 4.22-4.19 (1H, m),4.13-4.11 (1H, m), 3.13-3.07 (2H, m), 2.22-2.19 (1H, m), 1.88-1.84 (1H,m), 1.55-1.46 (2H, m), 1.11 (3H, s), 1.06 (3H, s). LC/MS: 507 [M + H].I-198 ¹H-NMR (DMSO-d₆) δ: 11.88 (1H, br s), 8.66 (1H, d, J = 7.3 Hz),8.24 (1H, s), 7.86-7.81 (3H, m), 7.71 (1H, d, J = 8.5 Hz), 7.48 (2H, m),7.28-7.24 (1H, m), 7.19-7.16 (2H, m), 7.09-7.08 (2H, m), 4.21-4.09 (2H,m), 3.93-3.83 (1H, m), 3.29-3.29 (1H, m), 3.10-3.08 (1H, m), 2.18-2.15(1H, m), 1.83 (3H, s), 1.67-1.44 (3H, m), 1.05 (3H, d, J = 6.7 Hz).LC/MS: 500 [M + H]. I-200 ¹H-NMR (DMSO-d₆) δ: 12.69 (1H, s), 8.70 (1H,d, J = 7.3 Hz), 8.22 (1H, s), 7.59-7.56 (2H, m), 7.49-7.47 (2H, m),7.27-7.25 (1H, m), 7.20-7.18 (3H, m), 7.03-7.01 (1H, m), 4.18 (1H, s),4.00-3.99 (1H, m), 1.82-1.81 (2H, m), 1.72-1.60 (4H, m), 1.46-1.40 (2H,m), 1.14 (3H, s). LC/MS: 477 [M + H]. I-201 ¹H-NMR (DMSO-d₆) δ: 12.71(1H, s), 8.92 (1H, d, J = 7.9 Hz), 8.22 (1H, s), 7.60-7.57 (2H, m),7.49-7.47 (2H, m), 7.26-7.24 (1H, m), 7.19-7.17 (3H, m), 7.03-7.01 (1H,m), 4.25 (1H, s), 4.24-4.22 (1H, m), 2.00-1.97 (2H, m), 1.66-1.64 (2H,m), 1.51-1.49 (4H, m), 1.14 (3H, s). LC/MS: 477 [M + H]. I-204 ¹H-NMR(DMSO-d₆) δ: 8.72 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.71 (1H, d, J =8.5 Hz), 7.52 (1H, s), 7.47-7.42 (3H, m), 7.22-7.20 (1H, m), 7.13-7.11(2H, m), 6.98 (1H, d, J = 2.4 Hz), 6.85 (1H, dd, J = 7.9, 2.4 Hz),4.22-4.10 (2H, m), 3.90-3.88 (1H, m), 3.32-3.29 (1H, m), 3.12-3.09 (1H,m), 2.28 (3H, s), 2.19-2.16 (1H, m), 1.83 (3H, s), 1.67-1.42 (3H, m),1.05 (3H, d, J = 6.7 Hz). LC/MS: 514 [M + H]. I-205 ¹H-NMR (DMSO-d₆) δ:12.69 (1H, s), 8.66 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.96 (1H, t, J =5.5 Hz), 7.85-7.83 (3H, m), 7.51-7.45 (2H, m), 7.28-7.24 (1H, m),7.17-7.16 (2H, m), 7.10-7.07 (2H, m), 4.15-4.13 (2H, m), 3.21-3.04 (4H,m), 2.15 (1H, m), 1.82 (3H, s), 1.77-1.73 (1H, m), 1.57-1.53 (1H, m),1.41-1.35 (1H, m). LC/MS: 486 [M + H]. I-207 ¹H-NMR (DMSO-d₆) δ: 12.73(1H, br s), 8.96 (1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.63-7.57 (2H, m),7.52-7.46 (2H, m), 7.29-7.16 (4H, m), 7.03 (1H, dd, J = 8.5, 1.8 Hz),4.69-4.61 (2H, m), 3.51 (2H, t, J = 6.1 Hz), 2.41-1.98 (5H, m). LC/MS:449 [M + H]. I-209 ¹H-NMR (DMSO-d₆) δ: 12.89 (1H, s), 8.94 (1H, s), 8.30(1H, s), 7.89-7.85 (3H, m), 7.50-7.47 (2H, m), 7.28-7.26 (2H, m),7.18-7.16 (2H, m), 7.10-7.09 (2H, m), 4.18-4.14 (2H, m), 4.01-3.99 (1H,m), 3.88-3.85 (1H, m), 3.40-3.37 (1H, m), 3.16-3.14 (1H, m), 2.18-2.16(1H, m), 1.66-1.47 (3H, m), 1.22-1.21 (3H, m), 1.10-1.09 (3H, m). LC/MS:530 [M + H]. I-211 ¹H-NMR (DMSO-d₆) δ: 12.78 (1H, br s), 8.80 (1H, brs), 8.26 (1H, s), 7.85-7.83 (3H, m), 7.60-7.59 (1H, m), 7.49-7.47 (2H,m), 7.26-7.25 (1H, m), 7.17-7.15 (2H, m), 7.09-7.08 (2H, m), 4.15-4.13(2H, m), 3.98 (1H, q, J = 6.7 Hz), 3.45-3.42 (1H, m), 3.20-3.13 (2H, m),2.17-2.15 (1H, m), 1.77-1.73 (1H, m), 1.57-1.54 (1H, m), 1.42-1.39 (1H,m), 1.21 (3H, d, J = 6.7 Hz). LC/MS: 516 [M + H]. I-212 ¹H-NMR (CDCl₃)δ: 9.20 (1H, d, J = 8.5 Hz), 8.29-8.25 (1H, m), 7.47-7.40 (3H, m),7.33-7.21 (3H, m), 7.13-7.07 (3H, m), 7.00-6.95 (1H, m), 4.53 (1H, brs), 3.94 (1H, br s), 3.81-3.73 (1H, m), 2.36-2.29 (1H, m), 2.21-2.13(2H, m), 1.95-1.40 (15H, m), 1.13 (3H, d, J = 6.1 Hz). LC/MS: 590 [M +H]. I-214 ¹H-NMR (CDCl₃) δ: 9.30 (1H, d, J = 7.9 Hz), 8.32-8.24 (1H, m),7.47-6.95 (10H, m), 5.68 (1H, d, J = 7.9 Hz), 4.47 (1H, s), 3.98 (1H, brs), 3.82-3.76 (1H, m), 2.40-2.32 (2H, m), 2.19-13 (1H, m), 1.93-1.41(15H, m), 1.15 (3H, d, J = 6.1 Hz). LC/MS: 604 [M + H]. (Synthesized bymethod described herein for Compound I-181) I-215 ¹H-NMR (DMSO-d₆) δ:12.78 (1H, s), 8.79 (1H, s), 8.27 (1H, s), 7.86-7.83 (3H, m), 7.49-7.47(2H, m), 7.26-7.24 (2H, m), 7.17-7.15 (2H, m), 7.10-7.08 (2H, m),4.18-4.14 (2H, m), 3.98-3.97 (1H, m), 3.88-3.85 (1H, m), 3.40-3.37 (1H,m), 3.15-3.12 (1H, m), 2.15 (1H, s), 1.63-1.49 (3H, m), 1.24 (3H, d, J =6.7 Hz), 1.10 (3H, d, J = 6.7 Hz). LC/MS: 530 [M + H]. I-217 ¹H-NMR(DMSO-d₆) δ: 12.82 (1H, br s), 8.85 (1H, br s), 8.28 (1H, s), 7.86-7.84(3H, m), 7.60-7.58 (1H, m), 7.49-7.47 (2H, m), 7.27-7.25 (1H, m),7.16-7.09 (4H, m), 4.16-4.14 (2H, m), 3.99-3.97 (1H, m), 3.44-3.41 (1H,m), 3.29-3.23 (1H, m), 3.15-3.12 (2H, m), 2.17-2.14 (1H, m), 1.78-1.74(1H, m), 1.60-1.57 (1H, m), 1.42-1.39 (1H, m), 1.22 (3H, d, J = 6.7 Hz).LC/MS: 516 [M + H].

Example 100:2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(3-methylthiophene-2-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-128)

2-(4-Methylpiperazin-1-yl)-N-(cis-4-((5-(3-methylthiophene-2-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-128) was made according to General Procedure B from(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-methyl-2-thienyl)methanone(128a) andN-(cis-4-aminocyclohexyl)-2-(4-methylpiperazin-1-yl)-acetamide (128b).¹H-NMR (DMSO-d₆) δ: 12.64 (1H, br s), 8.76 (1H, d, J=7.3 Hz), 8.22 (1H,s), 8.01 (1H, s), 7.83 (1H, d, J=4.9 Hz), 7.57 (1H, d, J=7.9 Hz), 7.15(1H, d, J=4.9 Hz), 4.22-4.24 (1H, m), 3.76-3.79 (1H, m), 2.90 (2H, s),2.35-2.41 (11H, m), 1.64-1.76 (8H, m), 2.07 (3H, s). LC/MS: 496 [M+H].

(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-methyl-2-thienyl)methanone(128a) was synthesized from 3-methylthiophen-2-carbonyl chloride. ¹H-NMR(DMSO-d₆) δ: 13.24 (1H, s), 8.73 (1H, s), 8.31 (1H, s), 7.88 (1H, d,J=4.9 Hz), 7.17 (1H, d, J=4.9 Hz), 2.45 (3H, s). LC/MS: 278 [M+H].

Condensation of 4-methylpiperazin-1-yl)acetic acid and tert-butylN-(cis-4-aminocyclohexyl)carbamate followed by Boc deprotection providedtert-butylN-(cis-4-((2-(4-methylpiperazin-1-yl)acetyl)amino)cyclohexyl)carbamate.¹H-NMR (CDCl₃) δ: 7.25 (1H, br s), 4.56 (1H, br s), 3.93-3.94 (1H, m),3.63 (1H, s), 2.99 (2H, s), 2.47-2.57 (8H, m), 2.32 (3H, s), 1.42-1.82(17H, m). LC/MS: 355 [M+H]. Subsequent Boc deprotection providedN-(cis-4-aminocyclohexyl)-2-(4-methylpiperazin-1-yl)-acetamide (128b).LC/MS: 255 [M+H].

Example 101:2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(2-methylthiophene-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-132)

2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(2-methylthiophene-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-132) was synthesized fromN-methoxy-N,2-dimethyl-thiophene-3-carboxamide (132a) and(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methyl-3-thienyl)methanone(132b). ¹H-NMR (DMSO-d₆) δ: 12.60 (1H, s), 9.04 (1H, d, J=7.3 Hz), 8.21(1H, s), 7.69 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.42 (1H, d, J=5.5 Hz),7.32 (1H, d, J=5.5 Hz), 4.24-4.26 (1H, m), 3.76-3.79 (1H, m), 2.91 (2H,s), 2.57 (3H, s), 2.33-2.42 (8H, m), 2.11 (3H, s), 1.63-1.81 (8H, m).LC/MS: 496 [M+H].

N-methoxy-N,2-dimethyl-thiophene-3-carboxamide (132a) was synthesizedfrom 2-methylthiophen-3-carboxylic acid by condensation reaction. ¹H-NMR(CDCl₃) δ: 7.12 (1H, d, J=4.9 Hz), 7.02 (1H, dd, J=4.9, 1.2 Hz), 3.56(3H, s), 3.32 (3H, s), 2.57 (3H, d, J=1.2 Hz). LC/MS: 186 [M+H].(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methyl-3-thienyl)methanone(132b) was synthesized from the Weinreb amide. LC/MS: 278 [M+H].

Example 102:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-methoxyphenyl)methanone(I-135)

Boc deprotection of Compound I-133 provided(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-methoxyphenyl)methanone(I-135). ¹H-NMR (DMSO-d₆) δ: 13.31 (1H, br s), 8.37 (1H, s), 8.10-8.01(4H, m), 7.50 (1H, t, J=7.9 Hz), 7.39 (1H, d, J=7.9 Hz), 7.32 (1H, s),7.27-7.24 (1H, m), 4.29-4.25 (1H, m), 3.84 (3H, s), 3.24-3.20 (1H, m),1.99-1.70 (8H, m). LC/MS: 366 [M+H].

Example 103:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-methoxy-2-methylphenyl)methanone(I-136)

Boc deprotection of Compound I-134 provided(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-methoxy-2-methylphenyl)methanone(I-136). ¹H-NMR (DMSO-d₆) δ: 8.36 (1H, s), 8.08-8.06 (3H, m), 7.67 (1H,br s), 7.28 (1H, d, J=8.5 Hz), 7.04 (1H, dd, J=8.2, 2.7 Hz), 7.00-7.00(1H, m), 4.29-4.27 (1H, m), 3.76 (3H, s), 3.24-3.21 (1H, m), 2.21 (3H,s), 1.99-1.73 (8H, m). LC/MS: 380 [M+H].

Example 104:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-5-methoxyphenyl)methanone(I-137)

(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-chloro-5-methoxyphenyl)methanonewas synthesized from methyl 2-chloro-5-methoxybenzoate, then tert-butylN-(cis-4-aminocyclohexyl)carbamate was introduced and the Boc group wasdeprotected to provide 1-137 according to General Procedure B followedby Boc deprotection. ¹H-NMR (DMSO-d₆) δ: 8.33 (1H, s), 8.07-7.97 (3H,m), 7.71 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.16-7.15 (1H, m), 7.13 (1H,d, J=3.1 Hz), 4.29-4.26 (1H, m), 3.80 (3H, s), 3.24-3.21 (1H, m),1.95-1.72 (8H, m). LC/MS: 400 [M+H].

Example 105:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-fluoro-3-methoxyphenyl)methanone(I-138)

(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-fluoro-3-methoxyphenyl)methanonewas synthesized from methyl 4-fluoro-3-methoxybenzoate, then tert-butylN-(cis-4-aminocyclohexyl)carbamate was introduced and the Boc group wasdeprotected to provide 1-138 according to General Procedure B followedby Boc deprotection. ¹H-NMR (DMSO-d₆) δ: 8.33 (1H, s), 8.04-7.97 (4H,m), 7.55 (1H, dd, J=8.5, 1.8 Hz), 7.44-7.38 (2H, m), 4.27-4.24 (1H, m),3.93 (3H, s), 3.22-3.19 (1H, m), 1.99-1.68 (8H, m). LC/MS: 384 [M+H].

Example 106:N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-139)

Acylation of Compound I-130 providedN-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-139). ¹H-NMR (DMSO-d₆) δ: 12.62 (1H, br s), 8.98 (1H, d, J=6.7 Hz),8.22 (1H, s), 7.89-7.83 (3H, m), 7.80 (1H, s), 7.51-7.46 (2H, m),7.28-7.23 (1H, m), 7.18-7.14 (2H, m), 7.12-7.07 (2H, m), 4.21 (1H, s),3.67-3.74 (1H, m), 1.85-1.57 (11H, m). LC/MS: 470 [M+H].

Example 107:N-(cis-4-((5-(3-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-140)

Acylation of Compound I-131 providedN-(cis-4-((5-(3-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-140). ¹H-NMR (DMSO-d₆) δ: 12.68 (1H, br s), 8.93-8.89 (1H, m), 8.22(1H, s), 7.87 (1H, d, J=7.3 Hz), 7.78 (1H, s), 7.57-7.55 (2H, m),7.47-7.42 (2H, m), 7.32-7.28 (2H, m), 7.22-7.18 (1H, m), 7.15-7.11 (2H,m), 4.22-4.17 (1H, m), 3.75-3.68 (1H, m), 1.81-1.55 (11H, m). LC/MS: 470[M+H].

Example 108:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(I-141)

SNAr reaction with(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo-[2,3-d]pyrimidin-5-yl)methanoneand tert-butyl N-(cis-4-aminocyclohexyl)carbamate followed by subsequentBoc deprotection provided(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(I-141). ¹H-NMR (DMSO-d₆) δ: 8.32 (1H, s), 8.04-7.95 (4H, m), 7.76 (1H,s), 7.60 (1H, d, J=8.5 Hz), 7.49 (2H, dd, J=8.5, 7.3 Hz), 7.27 (1H, t,J=7.3 Hz), 7.22 (1H, d, J=2.4 Hz), 7.20-7.17 (2H, m), 7.04 (1H, dd,J=8.2, 2.1 Hz), 4.28-4.25 (1H, m), 3.24-3.19 (1H, m), 1.97-1.70 (8H, m).LC/MS: 462 [M+H].

Example 109:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(2-methoxyethoxy)phenyl)methanone(I-143)

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(2-methoxyethoxy)phenyl)methanone(I-143) was synthesized from(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-(2-methoxyethoxy)phenyl)methanoneand tert-butyl N-(cis-4-aminocyclohexyl) carbamate according to GeneralProcedure B followed by Boc deprotection. ¹H-NMR (DMSO-d₆) δ: 8.34 (1H,s), 7.98-7.94 (4H, m), 7.84 (2H, d, J=8.5 Hz), 7.12 (2H, d, J=8.5 Hz),4.25-4.20 (3H, m), 3.72-3.69 (2H, m), 3.33 (3H, s), 3.23-3.18 (1H, m),1.98-1.69 (8H, m). LC/MS: 410 [M+H].

Example 110: Compound 144:rac-(4-((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-144) Step 1.6-((tert-butyl(diphenyl)-silyl)oxymethyl)tetrahydro-2H-pyran-3-one(144a)

Hydroboration oftert-butyl-(3,4-dihydro-2H-pyran-2-ylmethoxy)-diphenylsilane followed byoxidation of the secondary alcohol using Dess-Martin periodinaneprovided6-((tert-butyl(diphenyl)-silyl)oxymethyl)tetrahydro-2H-pyran-3-one(144a). ¹H-NMR (CDCl₃) δ: 7.70-7.65 (4H, m), 7.46-7.36 (6H, m), 4.14(1H, d, J=16.5 Hz), 3.94 (1H, d, J=16.5 Hz), 3.84-3.77 (2H, m),3.71-3.65 (1H, m), 2.65-2.57 (1H, m), 2.50-2.41 (1H, m), 2.15-2.08 (1H,m), 1.99-1.88 (1H, m), 1.07 (9H, s).

Step 2. rac-tert-butylN-[cis-6-(hydroxymethyl)tetrahydro-pyran-3-yl]carbamate (144b) andrac-tert-butylN-(trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (144c)

Reductive amination of Intermediate 144a using ammonium acetate/sodiumtriacetoxyborohydride followed by Boc protection of the generated aminogroup, and removal of TBDPS group provided intermediates 144b and 144c.

rac-tert-butyl N-[cis-6-(hydroxymethyl)tetrahydro-pyran-3-yl]carbamate(144b): ¹H-NMR (CDCl₃) δ: 5.20-5.14 (0.8H, m), 3.89 (1H, d, J=12.2 Hz),3.76-3.70 (1H, m), 3.65-3.43 (5H, m), 2.06-1.92 (2H, m), 1.78-1.68 (1H,m), 1.59-1.41 (10H, m).

rac-tert-butylN-(trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (144c):¹H-NMR (CDCl₃) δ: 4.35-4.25 (1H, m), 4.15-4.09 (1H, m), 3.65-3.44 (4H,m), 3.40-3.33 (1H, m), 3.02 (1H, t, J=10.7 Hz), 2.15-2.06 (2H, m),1.66-1.58 (1H, m), 1.52-1.40 (9H, m), 1.35-1.24 (1H, m).

Step 3.rac-(4-((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-144)

rac-(4-((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-144) was synthesized according to General Procedure B fromrac-tert-butyl N-(cis-6-(hydroxymethyl)tetrahydro-pyran-3-yl)carbamate144c (after Boc deprotection) and(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-phenoxy-phenyl)methanone.¹H-NMR (DMSO-d₆) δ: 12.62 (1H, br s), 9.23 (1H, d, J=7.9 Hz), 8.22 (1H,s), 7.86-7.83 (2H, m), 7.79 (1H, s), 7.50-7.45 (2H, m), 7.27-7.22 (1H,m), 7.18-7.15 (2H, m), 7.12-7.08 (2H, m), 4.65 (1H, t, J=5.8 Hz),4.33-4.28 (1H, m), 3.95-3.89 (1H, m), 3.66-3.61 (1H, m), 3.49-3.37 (2H,m), 1.97-1.82 (2H, m), 1.62-1.56 (2H, m). LC/MS: 445 [M+H].

Example 111:rac-(4-((trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-145)

rac-(4-((trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-145) was synthesized according to General Procedure B fromrac-tert-butyl N-(trans-6-(hydroxymethyl)tetrahydro-pyran-3-yl)carbamate144c (after Boc deprotection and(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-phenoxy-phenyl)methanone.¹H-NMR (DMSO-d₆) δ: 12.67 (1H, br s), 8.66 (1H, d, J=7.3 Hz), 8.24 (1H,s), 7.86-7.80 (3H, m), 7.51-7.45 (2H, m), 7.28-7.23 (1H, m), 7.18-7.14(2H, m), 7.11-7.06 (2H, m), 4.66 (1H, t, J=5.8 Hz), 4.18-4.09 (2H, m),3.45-3.35 (2H, m), 3.10 (1H, t, J=11.3 Hz), 2.20-2.13 (1H, m), 1.81-1.74(1H, m), 1.62-1.50 (1H, m), 1.44-1.31 (1H, m). LC/MS: 445 [M+H].

Example 112:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(3-fluorophenoxy)phenyl)methanone(I-148)

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(3-fluorophenoxy)phenyl)methanone(I-148) was synthesized according to General Procedure B from ethyl4-(3-fluorophenoxy)benzoate and tert-butylN-(4-aminocyclo-hexyl)carbamate followed by Boc deprotection. ¹H-NMR(DMSO-d₆) δ: 8.38 (1H, s), 8.09 (4H, s), 7.92 (2H, d, J=8.5 Hz), 7.52(1H, q, J=7.7 Hz), 7.20 (2H, d, J=8.5 Hz), 7.13-7.05 (2H, m), 7.01-6.98(1H, m), 4.29-4.24 (1H, m), 3.25-3.19 (1H, m), 2.00-1.71 (8H, m). LC/MS:446 [M+H].

Example 113:(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(benzyloxy)phenyl)methanone(I-154)

(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(benzyloxy)phenyl)methanone(I-154) was synthesized from(4-benzyloxyphenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(154a) and tert-butyl N-(4-aminocyclo-hexyl)carbamate according toGeneral Procedure B followed by Boc deprotection. ¹H-NMR (DMSO-d₆) δ:8.35 (1H, s), 8.02-7.99 (4H, m), 7.86 (2H, d, J=9.2 Hz), 7.50-7.49 (2H,m), 7.44-7.41 (2H, m), 7.38-7.35 (1H, m), 7.19 (2H, d, J=6.7 Hz), 5.24(2H, s), 4.25-4.23 (1H, m), 3.18-3.15 (1H, m), 1.99-1.71 (8H, m). LC/MS:442 [M+H].

(4-benzyloxyphenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(154a): ¹H-NMR (DMSO-d₆) δ: 13.21 (1H, s), 8.72 (1H, s), 8.14 (1H, s),7.86 (2H, d, J=9.2 Hz), 7.51-7.33 (5H, m), 7.16 (2H, d, J=9.2 Hz), 5.23(2H, s). LC/MS: 364 [M+H].

Example 114:(4-(((3R,6S)-6-((S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(I-166)

Removal of the phthaloyl group from2-((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-dione(166a) provided(((3R,6S)-6-((S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(I-166). ¹H-NMR (DMSO-d₆) δ: 8.60 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.58(1H, s), 7.55 (1H, d, J=8.5 Hz), 7.49-7.46 (2H, m), 7.26-7.24 (1H, m),7.19-7.17 (3H, m), 7.02-7.00 (1H, m), 4.22-4.18 (1H, m), 4.12-4.09 (1H,m), 3.13-3.03 (2H, m), 2.79-2.77 (1H, m), 2.19-2.16 (1H, m), 1.80-1.76(1H, m), 1.56-1.42 (2H, m), 0.98 (3H, q, J=6.7 Hz). LC/MS: 492 [M+H].

2-((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-dione(166a) was synthesized according to General Procedure A from(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)methanoneand2-((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-dione(166b). ¹H-NMR (DMSO-d₆) δ: 8.57 (1H, d, J=7.3 Hz), 8.21 (1H, s),7.88-7.83 (4H, m), 7.62 (1H, s), 7.56 (1H, d, J=8.5 Hz), 7.49-7.47 (2H,m), 7.26-7.24 (1H, m), 7.19-7.18 (3H, m), 7.02-7.00 (1H, m), 4.21-4.04(3H, m), 3.93-3.90 (1H, m), 3.00-2.98 (1H, m), 2.22-2.19 (1H, m),2.02-2.00 (1H, m), 1.71-1.57 (1H, m), 1.53-1.39 (4H, m). LC/MS: 622[M+H].

Boc deprotection ofN-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-tetrahydro-2H-pyran-3-yl)carbamateprovided2-((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-dione166b. LC/MS: 275 [M+H].

Example 115:(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((S)-1-(dimethylamino)ethyl)

tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-167)

Reductive methylation of Compound I-166 with formaline/sodiumtriacetoxyborohydride provided(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((S)-1-(dimethylamino)ethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-167). ¹H-NMR (DMSO-d₆) δ: 12.62 (1H, br s), 8.59 (1H, d, J=7.3 Hz),8.25 (1H, s), 7.62 (1H, s), 7.57 (1H, d, J=8.5 Hz), 7.49-7.47 (2H, m),7.27-7.25 (1H, m), 7.19-7.18 (3H, m), 7.03-7.01 (1H, m), 4.18-4.10 (2H,m), 3.39-3.37 (2H, m), 3.10-3.08 (1H, m), 2.21-2.17 (7H, m), 1.66-1.52(3H, m), 0.93-0.92 (3H, m). LC/MS: 520 [M+H].

Example 116:2-(dimethylamino)-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide (I-170)

Acylation of Compound I-130 provided2-(dimethylamino)-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide(I-170). ¹H-NMR (DMSO-d₆) δ: 12.65 (1H, s), 8.99 (1H, d, J=7.3 Hz), 8.22(1H, s), 7.85 (2H, d, J=8.5 Hz), 7.80 (1H, s), 7.61 (1H, d, J=7.3 Hz),7.48 (2H, t, J=7.9 Hz), 7.25 (1H, t, J=7.3 Hz), 7.16 (2H, d, J=7.9 Hz),7.10 (2H, d, J=8.5 Hz), 4.26-4.22 (1H, m), 3.78-3.74 (1H, m), 2.85 (2H,s), 2.19 (6H, s), 1.84-1.59 (8H, m). LC/MS: 513 [M+H].

Example 117:(2S,5R)—N-((2R,3R)-1,3-dihydroxybutan-2-yl)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide(I-175)

Condensation of(2S,5R)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxylicacid (LC/MS: 459 [M+H]) and (2R,3R)-2-aminobutane-1,3-diol provided(2S,5R)—N-((2R,3R)-1,3-dihydroxybutan-2-yl)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide (I-175). ¹H-NMR (DMSO-d₆) δ: 12.71(1H, s), 8.71 (1H, d, J=7.3 Hz), 8.25 (1H, s), 7.87-7.82 (3H, m),7.51-7.45 (2H, m), 7.25 (1H, t, J=7.3 Hz), 7.18-7.14 (2H, m), 7.09 (2H,d, J=8.5 Hz), 6.95 (1H, d, J=8.5 Hz), 4.82 (1H, d, J=4.9 Hz), 4.72 (1H,t, J=5.5 Hz), 4.28-4.17 (2H, m), 3.98-3.86 (2H, m), 3.65-3.58 (1H, m),3.44-3.22 (3H, m), 2.23-2.10 (2H, m), 1.74-1.46 (2H, m), 1.02 (3H, d,J=6.7 Hz). LC/MS: 546 [M+H].

Example 118:(2S,5R)—N—((R)-2,3-dihydroxypropyl)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide(I-176)

Condensation of (R)-3-aminopropane-1,2-diol and(2S,5R)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxylicacid and the applicable amine provided(2S,5R)—N—((R)-2,3-dihydroxypropyl)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide(I-176). ¹H-NMR (CDCl₃) δ: 12.70 (1H, s), 8.71 (1H, d, J=7.3 Hz), 8.25(1H, s), 7.87-7.82 (3H, m), 7.54-7.45 (3H, m), 7.28-7.23 (1H, m),7.19-7.14 (2H, m), 7.11-7.07 (2H, m), 4.87 (1H, d, J=5.5 Hz), 4.60 (1H,t, J=5.8 Hz), 4.27-4.14 (2H, m), 3.88 (1H, dd, J=11.0, 2.4 Hz),3.55-3.47 (1H, m), 3.36-3.21 (4H, m), 3.07-3.00 (1H, m), 2.23-2.06 (2H,m), 1.73-1.47 (2H, m). LC/MS: 532 [M+H].

Example 119:(2-chloro-4-phenoxyphenyl)(4-((trans-4-((dimethylamino)methyl)-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-177)

(2-chloro-4-phenoxyphenyl)(4-((trans-4-((dimethylamino)methyl)-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-177) was synthesized from4-amino-1-((dimethylamino)methyl)cyclohexan-1-ol (177a) and(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanoneaccording to General Procedure B.

Synthesis of 177a: Cbz deprotection of benzylN-(4-((dimethylamino)methyl)-4-hydroxy-cyclohexyl)carbamate (177b)provided 4-amino-1-((dimethylamino)methyl)cyclohexan-1-ol (177a).

Synthesis of 177b: BenzylN-(4-((dimethylamino)methyl)-4-hydroxy-cyclohexyl)carbamate (177b, cisstereoisomer) was synthesized from benzylN-(1-oxaspiro[2.5]octan-6-yl)carbamate (cis/trans mixture) anddimethylamine followed by stereoisomer separation (isomer A, B;configurations are unknown). Cbz group of isomer A (given transconfiguration for differentiation purposes only) was removed. ¹H-NMR(DMSO-d₆) δ: 12.69 (1H, s), 8.71 (1H, d, J=7.3 Hz), 8.22 (1H, s),7.59-7.58 (2H, m), 7.50-7.47 (2H, m), 7.27-7.24 (1H, m), 7.20-7.18 (3H,m), 7.02 (1H, dd, J=8.5, 2.4 Hz), 4.04-3.97 (2H, m), 2.30-2.25 (9H, m),1.85-1.83 (2H, m), 1.68-1.65 (4H, m), 1.45-1.42 (2H, m). LC/MS: 520[M+H].

Example 120:(2-chloro-4-phenoxyphenyl)(4-((cis-4-((dimethylamino)methyl)-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-178)

Cbz group of isomer B from Example 119 above (given cis configurationfor differentiation purposes only) was removed.(2-chloro-4-phenoxyphenyl)(4-((cis-4-((dimethylamino)methyl)-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-178) was synthesized from the resultant cis amine and(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanoneaccording to General Procedure B. ¹H-NMR (DMSO-d₆) δ: 12.70 (1H, s),8.89 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.60-7.59 (2H, m), 7.50-7.46 (2H,m), 7.27-7.23 (1H, m), 7.20-7.17 (3H, m), 7.02 (1H, dd, J=8.5, 2.4 Hz),4.22-4.05 (2H, m), 2.30-2.23 (9H, m), 2.00-1.95 (2H, m), 1.75-1.73 (2H,m), 1.48-1.46 (4H, m). LC/MS: 520 [M+H].

Example 121:N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(dimethylamino)acetamide(I-181)

Acylation of Compound I-141 providedN-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(dimethylamino)acetamide(I-181). ¹H-NMR (DMSO-d₆) δ: 12.73 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24(1H, s), 7.63-7.59 (3H, m), 7.48 (2H, t, J=7.6 Hz), 7.26 (1H, t, J=7.3Hz), 7.21-7.18 (3H, m), 7.03 (1H, dd, J=8.5, 2.4 Hz), 4.29-4.25 (1H, m),3.79-3.74 (1H, m), 2.86 (2H, s), 2.19 (6H, s), 1.81-1.60 (8H, m). LC/MS:547 [M+H].

Example 122:(2-chloro-4-(3-fluorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-182)

(2-chloro-4-(3-fluorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-182) was synthesized from according to General Procedure B usingchloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone and the applicableamine. ¹H-NMR (DMSO-d₆) δ: 12.78 (1H, s), 8.58 (1H, d, J=7.3 Hz), 8.25(1H, s), 7.68 (1H, s), 7.60 (1H, d, J=8.5 Hz), 7.50 (1H, q, J=7.9 Hz),7.31 (1H, d, J=2.4 Hz), 7.13-7.05 (3H, m), 7.02 (1H, dd, J=7.9, 1.8 Hz),4.60 (1H, d, J=5.5 Hz), 4.19-4.10 (2H, m), 3.53-3.46 (1H, m), 3.13-3.06(2H, m), 2.22-2.17 (1H, m), 1.95-1.90 (1H, m), 1.59-1.49 (1H, m),1.46-1.36 (1H, m), 1.08 (3H, d, J=6.1 Hz). LC/MS: 511 [M+H].

(2-chloro-4-(3-fluorophenoxy)phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas synthesized from methyl 2-chloro-4-(3-fluorophenoxy)benzoate. Methyl2-chloro-4-(3-fluorophenoxy)benzoate was synthesized from methyl2-chloro-4-fluorobenzoate and 3-fluorophenol.

Example 123:(2-chloro-4-(3-chlorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-183)

(2-chloro-4-(3-chlorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-183) was synthesized according to General Procedure B from(2-chloro-4-(3-chlorophenoxy)phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneand the applicable amine. ¹H-NMR (DMSO-d₆) δ: 12.78 (1H, s), 8.58 (1H,d, J=7.3 Hz), 8.25 (1H, s), 7.68 (1H, d, J=2.4 Hz), 7.60 (1H, d, J=8.5Hz), 7.48 (1H, t, J=8.2 Hz), 7.32-7.29 (3H, m), 7.17-7.14 (1H, m), 7.10(1H, dd, J=8.2, 2.1 Hz), 4.60 (1H, d, J=5.5 Hz), 4.19-4.10 (2H, m),3.53-3.46 (1H, m), 3.13-3.06 (2H, m), 2.22-2.18 (1H, m), 1.95-1.90 (1H,m), 1.60-1.49 (1H, m), 1.46-1.36 (1H, m), 1.08 (3H, d, J=6.1 Hz). LC/MS:527 [M+H].

(2-chloro-4-(3-chlorophenoxy)phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas synthesized from methyl 2-chloro-4-(3-chlorophenoxy)benzoate. Methyl2-chloro-4-(3-chlorophenoxy)benzoate was synthesized from methyl2-chloro-4-fluorobenzoate and 3-chlorophenol.

Example 124:(4-(((1R,3R)-3-aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-189)

Deprotection of Compound I-184 provided(4-(((1R,3R)-3-aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-189). ¹H-NMR (DMSO-d₆) δ: 13.35 (1H, br s), 9.75 (1H, br s), 8.39(1H, s), 8.16 (3H, br s), 8.04 (1H, br s), 7.90-7.84 (2H, m), 7.52-7.46(2H, m), 7.27 (1H, t, J=7.3 Hz), 7.17 (2H, d, J=7.9 Hz), 7.13-7.08 (2H,m), 4.73-4.63 (1H, m), 3.80-3.69 (1H, m), 2.40-2.32 (1H, m), 2.27-2.15(2H, m), 2.11-2.03 (1H, m), 1.79-1.66 (2H, m). LC/MS: 414 [M+H].

Example 125:(4-((cis-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-190)

Deprotection of Compound I-186 provided(4-((cis-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-190). ¹H-NMR (DMSO-d₆) δ: 13.13 (1H, br s), 9.52 (1H, br s), 8.33(1H, s), 8.17 (3H, br s), 7.99 (1H, s), 7.90-7.85 (2H, m), 7.52-7.46(2H, m), 7.30-7.25 (1H, m), 7.19-7.15 (2H, m), 7.13-7.09 (2H, m),4.55-4.43 (1H, m), 3.60-3.47 (1H, m), 2.86-2.77 (2H, m), 2.27-2.16 (2H,m). LC/MS: 400 [M+H].

Example 126:(4-((trans-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-191)

Deprotection of Compound I-185 provided(4-((trans-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone(I-191). ¹H-NMR (DMSO-d₆) δ: 13.09 (1H, br s), 8.34 (1H, s), 8.31-8.22(3H, br m), 7.98 (1H, br s), 7.88 (2H, d, J=9.2 Hz), 7.52-7.47 (2H, m),7.29-7.24 (1H, m), 7.19-7.15 (2H, m), 7.13-7.09 (2H, m), 4.86-4.75 (1H,m), 4.06-3.61 (1H, m), 2.71-2.60 (2H, m), 2.48-2.39 (2H, m). LC/MS: 400[M+H].

Example 127: Compound 192:N-((1R,3R)-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclopentyl)acetamide(I-192)

Acylation of Compound I-189 gaveN-((1R,3R)-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclopentyl)acetamide(I-192). ¹H-NMR (CDCl₃) δ: 9.17 (1H, d, J=7.3 Hz), 8.34 (1H, s),7.82-7.77 (2H, m), 7.60 (1H, s), 7.46-7.38 (2H, m), 7.21 (1H, t, J=7.3Hz), 7.14-7.04 (4H, m), 5.73 (1H, d, J=7.3 Hz), 4.76-4.63 (1H, m),4.54-4.43 (1H, m), 2.42-2.28 (2H, m), 2.20-2.00 (2H, m), 1.98 (3H, s),1.83-1.70 (1H, m), 1.62-1.49 (1H, m). LC/MS: 456 [M+H].

Example 128:(S)—N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxypropanamide(I-193)

Acylation of Compound I-141 provided(S)—N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxypropanamide(I-193). ¹H-NMR (DMSO-d₆) δ: 12.74 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24(1H, s), 7.63 (1H, s), 7.60 (1H, d, J=8.5 Hz), 7.51-7.43 (3H, m),7.27-7.24 (1H, m), 7.21-7.17 (3H, m), 7.03 (1H, dd, J=8.5, 2.4 Hz), 5.39(1H, d, J=5.5 Hz), 4.31-4.24 (1H, m), 4.00-3.93 (1H, m), 3.77-3.69 (1H,m), 1.59-1.83 (8H, m), 1.19 (3H, d, J=6.7 Hz). LC/MS: 534 [M+H].

Example 129:N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxy-2-methylpropanamide(I-194)

Acylation of compound I-141 gaveN-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-hydroxy-2-methylpropanamide(I-194). ¹H-NMR (DMSO-d₆) δ: 12.74 (1H, s), 8.96 (1H, d, J=7.3 Hz), 8.24(1H, s), 7.64 (1H, s), 7.61 (1H, d, J=8.5 Hz), 7.50-7.46 (2H, m),7.29-7.24 (2H, m), 7.21-7.17 (3H, m), 7.03 (1H, dd, J=8.5, 2.4 Hz), 5.46(1H, s), 4.32-4.25 (1H, m), 3.74-3.65 (1H, m), 1.60-1.83 (8H, m), 1.24(6H, s). LC/MS: 548 [M+H].

Example 130:N—((R)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide(I-195)

N—((R)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide(I-195) was synthesized according to General Procedure B fromN-((1R)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamidehydrochloride salt (195a) and(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)methanone.¹H-NMR (DMSO-d₆) δ: 12.77 (1H, s), 8.59 (1H, d, J=6.7 Hz), 8.25 (1H, s),7.80 (1H, d, J=8.5 Hz), 7.64 (1H, s), 7.57 (1H, d, J=8.5 Hz), 7.51-7.45(2H, m), 7.28-7.23 (1H, m), 7.20-7.17 (3H, m), 7.02 (1H, dd, J=8.2, 2.1Hz), 4.22-4.10 (2H, m), 3.82-3.76 (1H, m), 3.25-3.18 (1H, m), 3.15-3.08(1H, m), 2.22-2.15 (1H, m), 1.82-1.75 (4H, m), 1.60-1.41 (2H, m), 1.05(3H, d, J=6.7 Hz). LC/MS: 534 [M+H].

Synthesis ofN-((1R)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamidehydrochloride salt (195a):

tert-butylN-((3R,6S)-6-((1R)-1-azidoethyl)tetrahydro-2H-pyran-3-yl)carbamate wassynthesized from tert-butylN-((3R,6S)-6-((1S)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)carbamateunder Mitsunobu conditions using DPPA. LC/MS: 215 [M-t-Bu+2H]. Reductionof the Azide group via hydrogenation (LC/MS: 245 [M+H]) followed byacetylation provided tert-butylN-((3R,6S)-6-((1R)-1-acetamidoethyl)tetrahydro-2H-pyran-3-yl)carbamate.¹H-NMR (CDCl₃) δ: 5.85 (1H, br s), 4.24 (1H, br s), 4.10-4.07 (1H, m),4.04-3.96 (1H, m), 3.59-3.56 (1H, m), 3.27-3.25 (1H, m), 2.97-2.95 (1H,m), 2.12-2.06 (1H, m), 1.98 (3H, s), 1.50-1.47 (10H, m), 1.32-1.19 (2H,m), 1.09 (3H, d, J=6.7 Hz). LC/MS: 287 [M+H].

Boc deprotection of tert-butylN-((3R,6S)-6-((1R)-1-acetamidoethyl)tetrahydro-2H-pyran-3-yl)carbamateprovidedN-((1R)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamidehydrochloride salt (195a). ¹H-NMR (DMSO-d₆) δ: 8.21 (3H, br s), 7.81(1H, d, J=8.5 Hz), 4.05-4.02 (1H, m), 3.74-3.70 (1H, m), 3.32-3.20 (1H,m), 3.09-3.01 (2H, m), 2.08-2.05 (1H, m), 1.79 (3H, s), 1.69-1.65 (1H,m), 1.55-1.50 (1H, m), 1.33-1.28 (1H, m), 1.01 (3H, d, J=6.7 Hz). LC/MS:187 [M+H].

Example 131:N-(cis-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)acetamide (I-196)

Acylation of Compound I-190 gaveN-(cis-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)acetamide(I-196). ¹H-NMR (DMSO-d₆) δ: 12.70 (1H, br s), 8.98 (1H, d, J=6.1 Hz),8.23 (1H, s), 8.21 (1H, d, J=7.9 Hz), 7.88-7.81 (3H, m), 7.51-7.46 (2H,m), 7.29-7.24 (1H, m), 7.19-7.15 (2H, m), 7.09 (2H, d, J=8.5 Hz),4.42-4.30 (1H, m), 4.10-3.98 (1H, m), 2.77-2.67 (2H, m), 1.94-1.84 (2H,m), 1.78 (3H, s). LC/MS: 442 [M+H].

Example 132:(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-methyl-4-phenoxyphenyl)methanone(I-197)

(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-methyl-4-phenoxyphenyl)methanone(I-197) was synthesized according to General Procedure B from(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methyl-4-phenoxy-phenyl)-methanoneand the applicable amine. ¹H-NMR (DMSO-d₆) δ: 8.72 (1H, d, J=7.3 Hz),8.24 (1H, s), 7.51 (1H, s), 7.47-7.43 (3H, m), 7.21 (1H, t, J=7.6 Hz),7.12 (2H, d, J=7.9 Hz), 6.98 (1H, d, J=2.4 Hz), 6.85 (1H, dd, J=7.9, 2.4Hz), 4.61 (1H, d, J=5.5 Hz), 4.19-4.09 (2H, m), 3.53-3.46 (1H, m),3.13-3.05 (2H, m), 2.28 (3H, s), 2.21-2.17 (1H, m), 1.95-1.90 (1H, m),1.59-1.49 (1H, m), 1.46-1.36 (1H, m), 1.08 (3H, d, J=6.1 Hz). LC/MS: 473[M+H].

Example 133:N-(trans-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)acetamide(I-199)

Acylation of Compound I-191 providedN-(trans-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)acetamide(I-199). ¹H-NMR (DMSO-d₆) δ: 13.13 (1H, br s), 8.37-8.32 (2H, m), 8.00(1H, br s), 7.92-7.87 (2H, m), 7.52-7.46 (2H, m), 7.29-7.24 (1H, m),7.19-7.15 (2H, m), 7.11 (2H, d, J=8.5 Hz), 4.57 (1H, br s), 4.40-4.30(1H, m), 2.48-2.39 (2H, m), 2.38-2.28 (2H, m), 1.82 (3H, s). LC/MS: 442[M+H].

Example 134:(S)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propanamide(I-202)

Acylation of Compound I-130 provided(S)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propanamide(I-202). ¹H-NMR (DMSO-d₆) δ: 12.65 (1H, s), 9.00 (1H, d, J=7.3 Hz), 8.22(1H, s), 7.87-7.84 (2H, m), 7.80 (1H, s), 7.50-7.46 (3H, m), 7.25 (1H,t, J=7.3 Hz), 7.18-7.15 (2H, m), 7.09 (2H, d, J=8.5 Hz), 5.38 (1H, d,J=5.5 Hz), 4.27-4.22 (1H, m), 4.00-3.93 (1H, m), 3.75-3.69 (1H, m),1.83-1.63 (8H, m), 1.19 (3H, d, J=6.7 Hz). LC/MS: 500 [M+H].

Example 135:2-hydroxy-2-methyl-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propanamide(I-203)

Acylation of Compound I-130 provided2-hydroxy-2-methyl-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propanamide(I-203). ¹H-NMR (DMSO-d₆) δ: 12.65 (1H, s), 9.00 (1H, d, J=7.3 Hz), 8.23(1H, s), 7.87-7.84 (2H, m), 7.80 (1H, s), 7.50-7.46 (2H, m), 7.32 (1H,d, J=7.9 Hz), 7.25 (1H, t, J=7.3 Hz), 7.18-7.15 (2H, m), 7.11-7.08 (2H,m), 5.44 (1H, s), 4.27-4.23 (1H, m), 3.71-3.67 (1H, m), 1.81-1.63 (8H,m), 1.24 (6H, s). LC/MS: 514 [M+H].

Example 136:(R)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propanamide(I-206)

Acylation of Compound I-130 provided(R)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)propanamide(I-206). ¹H-NMR (DMSO-d₆) δ: 12.65 (1H, s), 9.00 (1H, d, J=7.9 Hz), 8.22(1H, s), 7.86 (2H, d, J=8.5 Hz), 7.80 (1H, s), 7.50-7.46 (3H, m), 7.25(1H, t, J=7.6 Hz), 7.17-7.15 (2H, m), 7.11-7.08 (2H, m), 5.38 (1H, d,J=5.5 Hz), 4.26-4.23 (1H, m), 3.99-3.93 (1H, m), 3.75-3.70 (1H, m),1.83-1.63 (8H, m), 1.19 (3H, d, J=6.7 Hz). LC/MS: 500 [M+H].

Example 137:(S)—N—((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(I-208)

(S)—N—((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(I-208) was synthesized according to General Procedure B from(S)—N—((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(208a). ¹H-NMR (DMSO-d₆) δ: 12.94 (1H, br s), 8.80 (1H, br s), 8.30 (1H,s), 7.71 (1H, s), 7.58 (1H, d, J=8.5 Hz), 7.50-7.47 (2H, m), 7.27-7.26(2H, m), 7.20-7.19 (3H, m), 7.04-7.02 (1H, m), 4.19-4.14 (2H, m),4.01-3.99 (1H, m), 3.88-3.86 (1H, m), 3.41-3.38 (1H, m), 3.18-3.15 (1H,m), 2.19-2.17 (1H, m), 1.65-1.52 (3H, m), 1.22 (3H, d, J=6.7 Hz), 1.10(3H, d, J=6.7 Hz). LC/MS: 564 [M+H].

Synthesis of(S)—N—((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(208a): Boc deprotection of tert-butylN-((3R,6S)-6-((1S)-1-(((2S)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-pyran-3-yl)carbamate(208b) provided amine 208a. LC/MS: 217 [M+H].

Synthesis of tert-butylN-((3R,6S)-6-((1S)-1-(((2S)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-pyran-3-yl)carbamate (208b): Acylation of tert-butylN-((3R,6S)-6-((1S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)carbamate with(2S)-2-hydroxypropanoic acid provided tert-butylN-((3R,6S)-6-((1S)-1-(((2S)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-pyran-3-yl)carbamate(208b). ¹H-NMR (CDCl₃) δ: 6.55 (1H, d, J=8.5 Hz), 4.26-4.18 (2H, m),4.09-4.07 (1H, m), 4.04-3.96 (1H, m), 3.52-3.49 (1H, m), 3.24-3.20 (1H,m), 3.00-2.92 (2H, m), 2.08-2.06 (1H, m), 1.47-1.43 (13H, m), 1.32-1.26(2H, m), 1.20 (3H, d, J=7.3 Hz). LC/MS: 317 [M+H].

Example 138:(S)—N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(I-210)

Acylation of tert-ButylN-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate with(2S)-2-hydroxypropanoic acid provided tert-butylN-((3R,6S)-6-((((2S)-2-hydroxypropanoyl)-amino)methyl)tetrahydro-2H-pyran-3-yl)carbamate(210a). LC/MS: 303 [M+H].

Boc deprotection of 210a provided(S)—N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(210b). LC/MS: 203 [M+H].

(S)—N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(I-210) was synthesized according to General Procedure B from(S)—N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(210b) and(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone.¹H-NMR (DMSO-d₆) δ: 12.92 (1H, br s), 8.78 (1H, br s), 8.31-8.28 (1H,m), 7.70 (1H, s), 7.59-7.57 (2H, m), 7.50-7.48 (2H, m), 7.27-7.26 (1H,m), 7.20-7.18 (3H, m), 7.02 (1H, dd, J=8.2, 2.1 Hz), 4.18-4.16 (2H, m),4.04-3.96 (1H, m), 3.45 (1H, s), 3.17-3.15 (3H, m), 2.19-2.16 (1H, m),1.78-1.75 (1H, m), 1.61-1.58 (1H, m), 1.43-1.40 (1H, m), 1.22-1.21 (3H,m). LC/MS: 550 [M+H].

Example 139:(R)—N—((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(I-213)

Acylation of tert-butylN-((3R,6S)-6-((1S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)carbamate with(2R)-2-hydroxypropanoic acid provided tert-butylN-((3R,6S)-6-((1S)-1-(((2R)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-pyran-3-yl)carbamate(213a). LC/MS: 317 [M+H].

Boc deprotection of tert-butylN-((3R,6S)-6-((1S)-1-(((2R)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-pyran-3-yl)carbamate(213a) provided(R)—N—((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(213b) LC/MS: 217 [M+H].

(R)—N—((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(I-213) was synthesized according to General Procedure B from(R)—N—((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamide(213b) and(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.¹H-NMR (DMSO-d₆) δ: 12.92 (1H, br s), 8.79 (1H, br s), 8.30 (1H, s),7.70 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.49-7.47 (2H, m), 7.25-7.21 (5H,m), 7.03-7.01 (1H, m), 4.19-4.14 (2H, m), 3.98-3.97 (1H, m), 3.88-3.85(1H, m), 3.41-3.38 (1H, m), 3.18-3.15 (1H, m), 2.21-2.18 (1H, m),1.69-1.45 (3H, m), 1.24 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=6.7 Hz).LC/MS: 564 [M+H].

Example 140:(R)—N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(I-216)

Acylation of tert-ButylN-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate with(2R)-2-hydroxypropanoic acid provided tert-butylN-((3R,6S)-6-((((2R)-2-hydroxypropanoyl)-amino)methyl)tetrahydro-2H-pyran-3-yl)carbamate(216a). LC/MS: 303 [M+H].

Boc deprotection of tert-butylN-((3R,6S)-6-((((2R)-2-hydroxypropanoyl)-amino)methyl)tetrahydro-2H-pyran-3-yl)carbamate(216a) provided(R)—N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(216b) LC/MS: 203 [M+H].

(R)—N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(I-216) was synthesized according to General Procedure B from(R)—N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide(216b) and(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.¹H-NMR (DMSO-d₆) δ: 12.89 (1H, br s), 8.75 (1H, br s), 8.29 (1H, s),7.69 (1H, s), 7.60-7.58 (2H, m), 7.49-7.47 (2H, m), 7.27-7.25 (1H, m),7.19-7.18 (3H, m), 7.03-7.02 (1H, m), 4.18-4.15 (2H, m), 3.98 (1H, q,J=6.5 Hz), 3.46-3.44 (1H, m), 3.27-3.25 (1H, m), 3.15-3.13 (2H, m),2.20-2.17 (1H, m), 1.78-1.75 (1H, m), 1.61-1.58 (1H, m), 1.42-1.40 (1H,m), 1.22 (3H, d, J=6.7 Hz). LC/MS: 550 [M+H].

Example 141: General Procedure C

Step 1. Intermediate 6-C

A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (6-A, 2.00 g, 10.6mmol), an aroyl chloride or heteroaroyl chloride (2-B, 1-3 eq.), andAlCl₃ (2-5 eq.) in nitrobenzene was heated at 70-90° C. for 1-6 hrs.Work-up and/or purification provided the corresponding aryl- orheteroaryl-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(6-C).

Step 2. Intermediate I-Y

A mixture of 6-C (1.00 g, 3.27 mmol), a primary amine (3-D, 1-4 eq.),and optionally a base (e.g., TEA, DIPEA, pyridine, and/or K₂CO₃ (1-5eq.)) in a solvent (e.g., DMF, NMP, IPA, n-BuOH or neat) was heated(70-160° C.) for 5-50 hrs or heated (100-220° C.) under microwaveradiation for 0.5-5 hrs. Work-up and/or purification provided thecorresponding aryl- orheteroaryl-(4-substituted-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone(I-Y).

Step 3. Compounds of Formula I-Z

A mixture of I-Y (70 mg, 0.145 mmol), a primary amine (6-D, 1-4 eq.),and optionally a base (e.g., TEA, DIPEA, pyridine, and/or K₂CO₃ (1-5eq.)) in a solvent (e.g., DMF, NMP, IPA, n-BuOH or neat) was heated(70-160° C.) for 5-50 hrs or heated (100-220° C.) under microwaveradiation for 0.5-5 hrs. Work-up and/or purification provided a compoundof Formula (I) (aryl- orheteroaryl-(2-substituted-amino-4-substituted-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-Z)).

The compounds of Formula (I) in Table 3 below were made according toGeneral Procedure C.

TABLE 3 Cmpd No. ¹H NMR and/or LC/MS data I-226 ¹H-NMR (CDCl₃) δ:12.73-12.90 (1H, m), 9.27-9.30 (1H, m), 8.38 (1H, d, J = 8.5 Hz), 7.79(2H, d, J = 7.6 Hz), 7.60-7.63 (2H, m), 7.53 (2H, t, J = 7.6 Hz),4.78-4.85 (1H, m), 3.85 (1H, dd, J = 11.3, 6.4 Hz), 3.61-3.71 (1H, m),3.35-3.57 (2H, m), 2.31-2.40 (1H, m), 2.05-2.15 (1H, m), 1.46 (9H, s).MS (ESI) m/z: 408 [M + H]⁺. I-230 ¹H-NMR (DMSO-d₆) δ: 12.67 (1H, s),8.82 (1H, t, J = 5.5 Hz), 8.24 (1H, s), 7.78 (2H, d, J = 7.3 Hz), 7.74(1H, s), 7.65 (1H, t, J = 7.3 Hz), 7.55 (2H, t, J = 7.6 Hz), 3.52 (2H,q, J = 6.5 Hz), 3.29-3.39 (4H, m), 2.20 (2H, t, J = 7.9 Hz), 1.78-1.95(4H, m). MS (ESI) m/z: 364 [M + H]⁺.

Example 142:(4-((cis-4-aminocyclohexyl)amino)-2-((1-methylpiperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-218)

Step 1.(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone (218b)

The mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (6-A, 2.00 g,10.6 mmol), 2-methylbenzoyl chloride (218a, 2.00 mL, 15.3 mmol), AlCl₃(5.00 g, 37.5 mmol) and nitrobenzene (30 mL) was heated at 70° C. for 3hrs. The resultant mixture was poured into ice and extracted with EtOAc.The extract was washed with water and brine, then dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. EtOAc and hexane was addedto the residue and precipitate was collected by filtration to give(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)-methanone(218b, 2.20 g, 7.18 mmol, 68%). LC/MS: 306 [M+H].

Step 2. tert-butylN-(cis-4-((2-chloro-5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate(218c)

The mixture of(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)-methanone(218b, 1.00 g, 3.27 mmol), tert-butyl N-(cis-4-aminocyclohexyl)carbamate(909 mg, 4.25 mmol), DIPEA (850 μL, 4.97 mmol) and IPA (15 mL) wasstirred at 160° C. for 1 h under microwave irradiation. The resultantmixture was diluted with chloroform and purified by columnchromatography over SiO₂ eluting with CHCl₃-MeOH to give tert-butylN-(cis-4-((2-chloro-5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate(218c, 1.40 g, 2.89 mmol, 89%) as colorless solid. LC/MS: 484 [M+H].

Step 3. tert-butylN-(cis-4-((5-(2-methylbenzoyl)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate(218d)

The mixture of tert-butylN-(cis-4-((2-chloro-5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate(218c, 70 mg, 0.145 mmol) and 1-methylpiperidin-4-amine (1 mL) wasstirred at 160° C. for 1 h under microwave irradiation. The resultantmixture was poured into water, extracted with CHCl₃, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resultingresidue was purified by column chromatography over SiO₂ eluting withCHCl₃-MeOH to give tert-butylN-(cis-4-((5-(2-methylbenzoyl)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate(218d, 68 mg, 0.121 mmol, 84%) as yellow oil. LC/MS: 562 [M+H].

Step 4.(4-((cis-4-aminocyclohexyl)amino)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone(I-218)

The mixture of tert-butylN-(cis-4-((5-(2-methylbenzoyl)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate(218d, 65 mg, 0.116 mmol) and dichloromethane (5 mL) was treated withTFA (2 mL) at ambient temperature and stirred for 1 hr. The mixture wasconcentrated in vacuo and the residue was purified by columnchromatography over SiO₂ with CHCl₃-MeOH. Then the product waslyophilized to give(4-((cis-4-aminocyclohexyl)amino)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone(15 mg, 0.0325 mmol, 28%) as pale yellow solid. ¹H-NMR (400 MHz, CD₃OD)δ: 7.42-7.26 (5H, m), 4.39-4.35 (1H, m), 3.85-3.79 (1H, m), 2.87-2.81(3H, m), 2.33 (3H, s), 2.29 (3H, s), 2.25-2.15 (2H, m), 2.08-1.97 (4H,m), 1.84-1.57 (8H, m). LC/MS: 462 [M+H].

Example 143:(2-amino-4-(cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-219)

(2-amino-4-(cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-219) was synthesized according to General Procedure C from4-methoxybenzyl amine (LC/MS: 585 [M+H]) followed by simultaneous Bocand benzyl deprotection. ¹H-NMR (CD₃OD) δ: 7.42-7.26 (5H, m), 4.39-4.35(1H, m), 2.80-2.74 (1H, m), 2.33 (3H, s), 2.01-1.94 (2H, m), 1.84-1.58(6H, m). LC/MS: 365 [M+H].

Example 144:(4-((cis-4-aminocyclohexyl)amino)-2-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-220)

(4-((cis-4-aminocyclohexyl)amino)-2-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-220) was synthesized according to General Procedure C fromN-methylamine (LC/MS: 479 [M+H]) followed by Boc deprotection. ¹H-NMR(CDCl₃) δ: 9.10 (1H, d, J=7.8 Hz), 7.33-7.28 (2H, m), 7.23-7.17 (2H, m),6.85 (1H, s), 4.73-4.69 (1H, m), 4.37-4.30 (1H, m), 2.92 (3H, d, J=5.1Hz), 2.80-274 (1H, m), 2.32 (3H, s), 1.97-1.92 (2H, m), 1.77-1.54 (6H,m). LC/MS: 379 [M+H].

Example 145:(4-((cis-4-aminocyclohexyl)amino)-2-(4-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-221)

(4-((cis-4-aminocyclohexyl)amino)-2-(4-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone(I-221) was synthesized according to General Procedure C fromN-methylpiperazine followed by Boc deprotection. ¹H-NMR (CD₃OD) δ: 9.06(1H, d, J=6.7 Hz), 7.00-7.42 (5H, m), 4.38-4.42 (1H, m), 3.79-3.82 (4H,m), 2.82-2.89 (1H, m), 2.48-2.51 (4H, m), 2.34 (3H, s), 2.33 (3H, s),2.02-2.06 (2H, m), 1.62-1.87 (6H, m). MS (ESI) m/z: 448 [M+H]⁺.

Example 146:N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide (I-222)

Acylation of Compound I-6 gaveN-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide(I-222). ¹H-NMR (DMSO-d₆) δ: 9.01 (1H, d, J=7.9 Hz), 8.23 (1H, s),7.53-7.62 (4H, m), 7.45-7.49 (2H, m), 4.30 (1H, br s), 3.73-3.83 (1H,m), 3.57 (1H, s), 2.89 (2H, s), 2.16-2.49 (8H, m), 2.02 (3H, s),1.60-1.84 (8H, m). MS (ESI) m/z: 510 [M+H]⁺.

Example 147:rac-(4-(3-aminopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone (I-223)

rac-(4-(3-aminopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone (I-223) was synthesized according to General ProcedureC from tert-butyl pyrrolidin-3-ylcarbamate followed by Boc deprotection.¹H-NMR (DMSO-d₆) δ: 8.16 (1H, s), 7.93 (2H, dd, J=7.6, 1.2 Hz), 7.68(1H, t, J=7.6 Hz), 7.56 (2H, t, J=7.6 Hz), 7.44 (1H, s), 3.66-3.71 (1H,m), 3.62 (1H, dd, J=11.3, 5.8 Hz), 3.50-3.56 (1H, m), 3.29-3.33 (1H, m),3.19 (1H, dd, J=11.0, 4.9 Hz), 1.79-1.87 (1H, m), 1.48-1.56 (1H, m). MS(ESI) m/z: 308 [M+H]⁺.

Example 148:rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(I-224)

Acylation of Compound I-223 providedrac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(I-224). ¹H-NMR (DMSO-d₆) δ: 12.34 (1H, s), 8.19 (1H, s), 7.97 (1H, d,J=6.1 Hz), 7.90 (2H, d, J=7.6 Hz), 7.68 (1H, t, J=7.6 Hz), 7.57 (2H, t,J=7.6 Hz), 7.45 (1H, d, J=1.8 Hz), 4.03-4.07 (1H, m), 3.55-3.77 (5H, m),3.44 (1H, dd, J=11.6, 4.3 Hz), 3.08-3.18 (2H, m), 1.93-1.98 (1H, m),1.89 (2H, d, J=10.0 Hz), 1.69-1.78 (2H, m), 1.36-1.39 (1H, m), 1.21-1.25(1H, m), 0.93-1.11 (2H, m). MS (ESI) m/z: 434 [M+H]⁺.

Example 149:rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-3-methoxypropanamide(I-225)

Acylation of Compound I-223 providedrac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-3-methoxypropanamide(I-225). ¹H-NMR (DMSO-d₆) δ: 12.73 (1H, br s), 9.05 (1H, dd, J=14.3, 6.4Hz), 8.28 (1H, d, J=1.8 Hz), 7.77-7.79 (3H, m), 7.65 (1H, t, J=7.6 Hz),7.55 (2H, t, J=7.6 Hz), 4.61-4.76 (1H, m), 3.90 (0.5H, dd, J=10.4, 6.1Hz), 3.65-3.73 (1.5H, m), 3.45-3.57 (4H, m), 3.35-3.39 (1H, m), 3.20(1.5H, s), 3.18 (1.5H, s), 2.46-2.54 (2H, m), 2.21-2.38 (1H, m),1.90-2.09 (1H, m). MS (ESI) m/z: 394 [M+H]⁺.

Example 150:rac-phenyl(4-(pyrrolidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-227)

rac-phenyl(4-(pyrrolidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-227) was synthesized according to General Procedure C followed by Bocdeprotection. ¹H-NMR (DMSO-d₆) δ: 13.01 (1H, br s), 9.14-9.25 (3H, m),8.36 (1H, s), 7.89 (1H, s), 7.80 (2H, dd, J=7.6, 1.2 Hz), 7.68 (1H, t,J=7.6 Hz), 7.57 (2H, t, J=7.6 Hz), 4.73-4.81 (1H, m), 3.58-3.63 (1H, m),3.37-3.45 (1H, m), 3.28-3.36 (1H, m), 3.18-3.25 (1H, m), 2.39-2.47 (1H,m), 2.00-2.09 (1H, m).

Example 151: Compound 228:rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one(I-228)

Acylation of Compound I-227 providedrac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one(I-228). ¹H-NMR (DMSO-d₆) δ: 12.73 (1H, br s), 9.05 (1H, dd, J=11.0, 6.7Hz), 8.28 (1H, d, J=4.3 Hz), 7.76-7.78 (3H, m), 7.65 (1H, t, J=7.6 Hz),7.55 (2H, t, J=7.6 Hz), 4.62-4.75 (1H, m), 3.62-3.86 (4H, m), 3.40-3.57(2H, m), 3.33-3.30 (1H, m), 3.15-3.27 (2H, m), 1.85-2.34 (5H, m),1.51-1.60 (2H, m), 1.10-1.24 (2H, m). MS (ESI) m/z: 434 [M+H]⁺.

Example 152:rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-methoxypropan-1-one(I-229)

Acylation of Compound I-227 providedrac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-methoxypropan-1-one(I-229). ¹H-NMR (DMSO-d₆) δ: 12.73 (1H, br s), 9.05 (1H, dd, J=14.3, 6.4Hz), 8.28 (1H, d, J=1.8 Hz), 7.77-7.79 (3H, m), 7.65 (1H, t, J=7.6 Hz),7.55 (2H, t, J=7.6 Hz), 4.61-4.76 (1H, m), 3.90 (0.5H, dd, J=10.4, 6.1Hz), 3.65-3.73 (1.5H, m), 3.45-3.57 (4H, m), 3.35-3.39 (1H, m), 3.20(1.5H, s), 3.18 (1.5H, s), 2.46-2.54 (2H, m), 2.21-2.38 (1H, m),1.90-2.09 (1H, m). MS (ESI) m/z: 394 [M+H]⁺.

General Procedure D

To a solution of pyrrolo[2,3-d]pyrimidine (8-A)(1 eq.) in DMF (1 mL/0.28mmol) at room temperature was added potassium carbonate (2 eq.) andSEM-Cl (1.2 eq.). The reaction mixture was stirred at room temperaturefor 3 hours. The reaction mixture was then poured into 1:1 water/EtOAcand partitioned. The aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated to dryness. The residue was purified by flashchromatography on silica gel eluting with 30-100% EtOAc/hexanes toafford the product.

General Procedure E

A suspension of the arylnitro compound (9-A) (1 eq.), ammonium chloride(10 eq. and iron (5 eq) in EtOH (1 mL/0.12 mmol) and water (1 mL/0.25mmol) was heated to 80° C. for 2 hours. Upon cooling to roomtemperature, methanol was added, the reaction mixture was vigorouslystirred for 30 min, filtered through Celite and washed with methanol andEtOAc. The filtrate was concentrated to dryness. The residue wastriturated in water and the solids were collected by filtration, driedunder high vacuum to afford the corresponding arylamine.

General Procedure F

To a solution of the arylamine (10-A) (1 eq.) in DMF (2 mL/0.16 mmol)were added carboxylic acid (1.5 eq.), HATU (1.2 eq.) and DIPEA (2.5 eq.)and the reaction mixture was allowed to stir at room temperature for 18hours or heated to 40-50° C. for 3-90 hours. Upon cooling to roomtemperature, the reaction mixture diluted with aqueous saturated NaHCO₃and ethyl acetate. The layers were partitioned and the aqueous layer wasextracted with ethyl acetate. The combined organic layer were washedwith brine, dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure. The crude product was adsorbed ontosilica gel for purification by ISCO CombiFlash (eluted with 0-10%MeOH/DCM or EtOAc/hexanes) or purified by reverse phase C18 columnchromatography (10-95% acetonitrile in water, 0.1% formic acid) to yieldthe amide product (11-A).

General Procedure G

To a solution of the arylamine (1 eq.) in THF (2 mL/0.343 mmol) wereadded isocyanate (1.2 eq.) and DIPEA (2.5 eq.). The reaction mixture wasallowed to stir at room temperature for 18 hours. The volatiles wereremoved under reduced pressure and the residue was adsorbed in silicagel purification by ISCO CombiFlash eluting with EtOAc/hexanes to yieldthe urea product.

General Procedure H

To a solution of SEM-protected substrate (8-A) (1 eq.) in DCM (1mL/0.044 mmol) was added a solution of HCl (4 N in dioxane, 60-81 eq.).The mixture was heated to 40° C. for 18 hours and concentrated todryness under reduced pressure. The residue was diluted with 10 mL ofDCM/MeOH/NH₄OH (90:9:1) and adsorbed onto silica gel for purification byflash chromatography on silica gel eluting with MeOH/DCM (9:1) andDCM/MeOH/NH₄OH (90:9:1) to yield the deprotected product.

Example 153: Synthesis of N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide(I-601)

N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamidewas synthesized according to General Scheme 4, General Procedures A, D,E, F, H. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.79 (s; 1H); 10.50 (s; 1H); 8.59(d; J 7.06 Hz; 1H); 8.26 (s; 1H); 8.01 (d; J 2.53 Hz; 1H); 7.93-7.97 (m;3H); 7.53-7.63 (m; 5H); 4.66 (t; J 5.58 Hz; 1H); 4.14-4.19 (m; 2H);3.34-3.44 (m; 3H); 3.14 (t; J 11.24 Hz; 1H); 2.18-2.22 (m; 1H);1.77-1.81 (m; 1H); 1.57-1.61 (m; 1H); 1.37-1.43 (m; 1H). LCMS [M+H]⁺:506.2

Example 154: Synthesis ofN-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide(I-602)

N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamidewas synthesized according to General Scheme 4, General Procedures A, D,E, F, H. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.75 (s; 1H); 10.46 (s; 1H); 8.56(d; J=7.05 Hz; 1H); 8.25 (s; 1H); 7.81 (d; J=2.54 Hz; 1H); 7.70 (dd;J=8.80; 2.56 Hz; 1H); 7.58 (s; 1H); 7.52 (d; J=8.78 Hz; 1H); 7.32 (d;J=4.37 Hz; 4H); 7.23-7.26 (m; 1H); 4.66 (t; J=5.15 Hz; 1H); 4.12-4.18(m; 2H); 3.65 (s; 2H); 3.34-3.41 (m; 3H); 3.12 (t; J=11.05 Hz; 1H);2.17-2.21 (m; 1H); 1.76-1.80 (m; 1H); 1.56-1.60 (m; 1H); 1.36-1.42 (m;1H). LCMS [M+H]⁺: 520.2.

Example 155: Synthesis ofN-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4-carboxamide(I-603)

N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4-carboxamidewas synthesized according to General Scheme 4, General Procedures A, D,E, F, H. ¹H NMR (DMSO-d₆, 400 mHz): δ 10.22 (s; 1H); 8.56-8.58 (m; 1H);8.24 (s; 1H); 7.83 (d; J=2.52 Hz; 1H); 7.71 (dd; J=8.79; 2.55 Hz; 1H);7.56 (s; 1H); 7.50 (d; J=8.77 Hz; 1H); 4.60-4.71 (m; 1H); 4.10-4.18 (m;2H); 3.88-3.92 (m; 2H); 3.36-3.41 (m; 5H); 3.09-3.16 (m; 1H); 2.52-2.63(m; 1H); 2.16-2.21 (m; 1H); 1.54-1.77 (m; 6H); 1.33-1.43 (m; 1H). NH ofindole not observed. 0.2 equiv. of formic acid (8.36 ppm) observed. LCMS[M+H]⁺: 514.2.

Example 156: Synthesis ofN-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)thiazole-5-carboxamide(I-604)

N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)thiazole-5-carboxamidewas synthesized according to General Scheme 4, General Procedures A, D,E, F, H. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.83 (s; 1H); 10.71 (s; 1H); 9.33(s; 1H); 8.70 (s; 1H); 8.61 (d; J=6.93 Hz; 1H); 8.27 (s; 1H); 7.92 (d;J=2.53 Hz; 1H); 7.89 (dd; J=8.75; 2.59 Hz; 1H); 7.64 (s; 1H); 7.61 (d;J=8.73 Hz; 1H); 4.13-4.19 (m; 2H); 3.39-3.46 (m; 5H); 3.14 (t; J=11.03Hz; 1H); 2.18-2.22 (m; 1H); 1.76-1.80 (m; 1H); 1.57-1.63 (m; 1H);1.37-1.43 (m; 1H). OH of alcohol not observed. LCMS [M+H]⁺: 513.1.

Example 157: Synthesis ofN-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropane-1-carboxamide(I-605)

N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropane-1-carboxamidewas synthesized according to General Scheme 4, General Procedures A, D,E, F, H. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.75 (s; 1H); 9.32 (s; 1H); 8.55(d; J=7.12 Hz; 1H); 8.24 (s; 1H); 7.74-7.76 (m; 2H); 7.55 (s; 1H);7.47-7.49 (m; 1H); 7.33-7.40 (m; 4H); 7.26-7.30 (m; 1H); 4.65 (t; J=5.58Hz; 1H); 4.12-4.16 (m; 2H); 3.36-3.44 (m; 3H); 3.11 (t; J=11.35 Hz; 1H);2.16-2.20 (m; 1H); 1.76-1.80 (m; 1H); 1.54-1.58 (m; 1H); 1.37-1.47 (m;3H); 1.10-1.13 (m; 2H). LCMS [M+H]⁺: 546.2.

Example 158: Synthesis ofN-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamide(I-606)

N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamidewas synthesized according to General Scheme 4, General Procedures A, D,E, F, H. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.79 (s; 1H); 10.88 (s; 1H); 8.61(d; J=7.06 Hz; 1H); 8.41 (s; 1H); 8.26 (s; 1H); 8.11-8.15 (m; 2H); 7.85(s; 1H); 7.63 (s; 1H); 7.57 (d; J=8.58 Hz; 1H); 4.66 (t; J=5.51 Hz; 1H);4.14-4.19 (m; 2H); 3.35-3.42 (m; 3H); 3.14 (t; J=11.12 Hz; 1H);2.81-2.83 (m; 4H); 2.18-2.22 (m; 1H); 1.76-1.80 (m; 5H); 1.57-1.63 (m;1H); 1.37-1.41 (m; 1H). LCMS [M+H]⁺: 561.3.

Example 159: Synthesis ofN-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)isoquinoline-1-carboxamide(I-607)

N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)isoquinoline-1-carboxamidewas synthesized according to General Scheme 4, General Procedures A, D,E, F, H. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.86 (s; 1H); 11.19 (s; 1H); 8.92(d; J=8.63 Hz; 1H); 8.71 (d; J=5.58 Hz; 1H); 8.67 (d; J=7.07 Hz; 1H);8.33 (s; 1H); 8.21 (d; J=2.55 Hz; 1H); 8.18 (s; 1H); 8.16 (d; J=2.20 Hz;1H); 8.12 (dd; J=8.80; 2.56 Hz; 1H); 7.93 (t; J=7.59 Hz; 1H); 7.83 (t;J=7.81 Hz; 1H); 7.74 (s; 1H); 7.69 (d; J=8.78 Hz; 1H); 4.73 (t; J=5.52Hz; 1H); 4.20-4.26 (m; 2H); 3.41-3.51 (m; 3H); 3.21 (t; J=11.10 Hz; 1H);2.25-2.29 (m; 1H); 1.83-1.87 (m; 1H); 1.65-1.69 (m; 1H); 1.44-1.50 (m;1H). LCMS [M+H]⁺: 557.2.

Example 160: Synthesis of1-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-phenylurea(I-608)

1-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-phenylureawas synthesized according to General Scheme 4, General Procedures A, D,E, F, G. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.74 (br s; 1H); 9.38 (s; 1H);9.19 (s; 1H); 8.60 (d; J=7.05 Hz; 1H); 8.25 (s; 1H); 7.70 (d; J=2.59 Hz;1H); 7.57-7.60 (m; 2H); 7.44-7.48 (m; 3H); 7.24-7.28 (m; 2H); 6.96 (t;J=7.37 Hz; 1H); 4.66 (t; J=5.36 Hz; 1H); 4.12-4.19 (m; 2H); 3.35-3.42(m; 3H); 3.11-3.17 (m; 1H); 2.17-2.22 (m; 1H); 1.76-1.80 (m; 1H);1.53-1.64 (m; 1H); 1.32-1.43 (m; 1H). Contained 0.2 equiv. of formicacid. LCMS [M+H]⁺: 521.1.

Example 161: Synthesis of1-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-(pyridin-3-yl)urea(I-609)

1-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-(pyridin-3-yl)ureawas synthesized according to General Scheme 4, General Procedures A, D,E, F, G. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.76 (br s; 1H); 9.56 (s; 1H);9.44 (s; 1H); 8.59-8.62 (m; 2H); 8.25 (s; 1H); 8.18 (dd; J=4.67; 1.43Hz; 1H); 7.92 (ddd; J=8.36; 2.58; 1.46 Hz; 1H); 7.70 (d; J=2.59 Hz; 1H);7.59-7.62 (m; 2H); 7.49 (d; J=8.77 Hz; 1H); 7.30 (dd; J=8.34; 4.67 Hz;1H); 4.66 (s; 1H); 4.12-4.19 (m; 2H); 3.37-3.45 (m; 3H); 3.10-3.16 (m;1H); 2.18-2.22 (m; 1H); 1.77-1.81 (m; 1H); 1.54-1.64 (m; 1H); 1.33-1.43(m; 1H). LCMS [M+H]⁺: 522.2.

Example 162: Synthesis of3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide(I-236)

3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamidewas synthesized according to General Scheme 5, using aniline as theamine. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.80 (br s; 1H); 10.45 (s; 1H);8.56 (d; J=7.03 Hz; 1H); 8.27 (s; 1H); 8.17 (d; J=1.53 Hz; 1H); 8.04(dd; J=7.92; 1.59 Hz; 1H); 7.79 (d; J=8.03 Hz; 2H); 7.74 (d; J=7.89 Hz;1H); 7.59 (s; 1H); 7.39 (t; J=7.77 Hz; 2H); 7.12-7.16 (m; 1H); 4.66 (t;J=5.42 Hz; 1H); 4.08-4.17 (m; 2H); 3.40-3.49 (m; 3H); 3.11-3.18 (m; 1H);2.17-2.22 (m; 1H); 1.78-1.88 (m; 1H); 1.52-1.65 (m; 1H); 1.32-1.45 (m;1H). LCMS [M+H]⁺: 506.2.

Example 163: Synthesis of3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide (I-610)

3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamidewas synthesized according to General Scheme 5 using 2-methoxyethylamine.¹H NMR (DMSO-d₆, 400 mHz): δ 12.78 (s; 1H); 8.78-8.80 (m; 1H); 8.55 (d;J=7.09 Hz; 1H); 8.26 (s; 1H); 8.05 (d; J=1.51 Hz; 1H); 7.93 (dd; J=7.92;1.56 Hz; 1H); 7.66 (d; J=7.91 Hz; 1H); 7.58 (s; 1H); 4.66 (t; J=5.57 Hz;1H); 4.15-4.17 (m; 2H); 3.35-3.50 (m; 7H); 3.28 (s; 3H); 3.13 (t;J=11.33 Hz; 1H); 2.18 (s; 1H); 1.78 (d; J=12.89 Hz; 1H); 1.58 (d;J=12.92 Hz; 1H); 1.38 (d; J=13.18 Hz; 1H). LCMS [M+H]⁺: 488.2.

Example 164: Synthesis of(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)methanone (I-611)

(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)methanonewas synthesized according to General Scheme 5, using morpholine as theamine. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.80 (s; 1H); 8.56 (d; J=7.11 Hz;1H); 8.26 (s; 1H); 7.66 (s; 1H); 7.63 (s; 1H); 7.62 (d; J=6.31 Hz; 1H);7.46 (dd; J=7.74; 1.45 Hz; 1H); 4.66 (t; J=5.58 Hz; 1H); 4.16 (d; J=9.36Hz; 2H); 3.58-3.69 (m; 6H); 3.34-3.44 (m; 5H); 3.13 (t; J=11.37 Hz; 1H);2.17-2.20 (m; 1H); 1.77-1.81 (m; 1H); 1.55-1.59 (m; 1H); 1.36-1.39 (m;1H). LCMS [M+H]⁺: 500.2.

Example 165: Synthesis of(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)methanone (I-612)

(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)methanonewas synthesized according to General Scheme 5, using morpholine as theamine. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.77 (br s; 1H); 8.55 (d; J=7.06Hz; 1H); 8.25 (s; 1H); 7.57-7.69 (m; 4H); 4.66 (s; 1H); 4.16 (m; 2H);3.32-3.57 (m; 11H); 3.12 (t; J=11.26 Hz; 1H); 2.19 (d; J=11.57 Hz; 1H);1.76-1.79 (m; 1H); 1.52-1.61 (m; 1H); 1.38 (q; J=11.99 Hz; 1H). LCMS[M+H]⁺: 500.2, 502.2.

Example 166: Synthesis of3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)benzamide (I-613)

3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)benzamidewas synthesized according to General Scheme 5, using2-morpholinoethan-1-amine. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.78 (s; 1H);8.67-8.70 (m, 1H); 8.55 (d; J 7.05 Hz; 1H); 8.26 (s; 1H); 8.02 (d; J1.52 Hz; 1H); 7.90 (dd; J=7.94; 1.56 Hz; 1H); 7.66 (d; J=7.91 Hz; 1H);7.55 (s; 1H); 4.66 (t; J 5.58 Hz; 1H); 4.14-4.18 (m; 2H); 3.58 (t; J4.51 Hz; 4H); 3.34-3.45 (m; 6H); 3.13 (t; J=11.30 Hz; 1H); 2.39-2.46 (m;5H); 2.16-2.21 (m; 1H); 1.77-1.80 (m; 1H); 1.55-1.59 (m; 1H); 1.36-1.41(m; 1H). LCMS [M+H]⁺: 543.3.

Example 167: Synthesis of3-chloro-N-(3-cyanophenyl)-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide(I-614)

3-Chloro-N-(3-cyanophenyl)-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamidewas synthesized according to General Scheme 5, using3-aminobenzonitrile. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.74-12.89 (bs; 1H);10.76 (s; 1H); 8.55 (d; J 7.05 Hz; 1H); 8.26-8.28 (m; 2H); 8.18 (d; J1.57 Hz; 1H); 8.03-8.08 (m; 2H); 7.76 (d; J 7.91 Hz; 1H); 7.62 (d; J4.90 Hz; 2H); 7.59 (s; 1H); 4.64-4.67 (m; 1H); 4.15-4.19 (m; 2H);3.35-3.44 (m; 3H); 3.10-3.16 (m; 1H); 2.15-2.22 (m; 1H); 1.76-1.81 (m;1H); 1.52-1.64 (m; 1H); 1.33-1.44 (m; 1H). LCMS [M+H]⁺: 531.2.

Example 168: Synthesis of3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide(I-256)

3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamidewas synthesized according to General Scheme 5, using pyridine-3-amine.¹H NMR (DMSO-d₆, 400 mHz): δ 12.79 (br s; 1H); 10.66 (s; 1H); 8.95 (s;1H); 8.55 (d; J=7.01 Hz; 1H); 8.36 (dd; J=4.66; 1.81 Hz; 1H); 8.27 (s;1H); 8.19-8.22 (m; 2H); 8.03-8.06 (m; 1H); 7.75-7.78 (m; 1H); 7.60 (s;1H); 7.43 (dd; J=8.30; 4.69 Hz; 1H); 4.66 (t; J=5.50 Hz; 1H); 4.11-4.29(m; 2H); 3.33-3.42 (m; 3H); 3.10-3.17 (m; 1H); 2.16-2.23 (m; 1H);1.76-1.81 (m; 1H); 1.54-1.64 (m; 1H); 1.33-1.44 (m; 1H). LCMS [M+H]⁺:507.2.

Example 169: Synthesis of(2-chloro-4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-615)

(2-Chloro-4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas synthesized according to General Scheme 5, using1,2,3,4-tetrahydroisoquinoline. ¹H NMR (DMSO-d₆, 400 mHz): δ 8.57-8.59(m; 1H); 8.24-8.26 (m; 1H); 7.63-7.70 (m; 3H); 7.49-7.53 (m; 1H);7.10-7.29 (m; 4H); 4.78-4.79 (m; 1H); 4.62-4.67 (m; 2H); 4.13-4.19 (m;2H); 3.82-3.89 (m; 1H); 3.61-3.64 (m; 1H); 3.40-3.44 (m; 3H); 3.10-3.16(m; 1H); 2.85-2.91 (m; 2H); 2.16-2.21 (m; 1H); 1.77-1.80 (m; 1H);1.53-1.60 (m; 1H); 1.36-1.44 (m; 1H). NH of indole not observed. LCMS[M+H]⁺: 546.02.

Example 170: Synthesis of(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone(I-616)

(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanonewas synthesized according to General Scheme 5, using1-(pyridin-2-yl)piperazine. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.82 (s; 1H);8.57 (d; J=7.09 Hz; 1H); 8.27 (s; 1H); 8.13-8.14 (m; 1H); 7.68 (s; 1H);7.66 (d; J=1.43 Hz; 1H); 7.64 (d; J=7.72 Hz; 1H); 7.55-7.59 (m; 1H);7.50 (dd; J=7.75; 1.44 Hz; 1H); 6.87 (d; J=8.63 Hz; 1H); 6.68 (dd;J=7.05; 4.93 Hz; 1H); 4.66 (t; J=5.58 Hz; 1H); 4.12-4.19 (m; 2H);3.44-3.78 (m; 8H); 3.34-3.42 (m; 3H); 3.13 (t; J=11.28 Hz; 1H);2.18-2.22 (m; 1H); 1.76-1.80 (m; 1H); 1.56-1.60 (m; 1H); 1.37-1.43 (m;1H). LCMS [M+H]⁺: 576.3.

Example 171: Synthesis of(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)methanone(I-617)

(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)methanonewas synthesized according to General Scheme 5, using piperidine. ¹H NMR(DMSO-d₆, 400 mHz): δ 12.79 (s; 1H); 8.57 (d; J=7.10 Hz; 1H); 8.26 (s;1H); 7.67 (s; 1H); 7.61 (d; J=7.73 Hz; 1H); 7.57 (d; J=1.40 Hz; 1H);7.42 (dd; J=7.73; 1.46 Hz; 1H); 4.66 (t; J=5.59 Hz; 1H); 4.12-4.17 (m;2H); 3.53-3.63 (m; 2H); 3.34-3.44 (m; 5H); 3.13 (t; J=11.27 Hz; 1H);2.17-2.21 (m; 1H); 1.77-1.81 (m; 1H); 1.49-1.62 (m; 7H); 1.36-1.42 (m;1H). LCMS [M+H]⁺: 498.2.

Example 172: Synthesis ofN-benzyl-3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide(I-618)

N-Benzyl-3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamidewas synthesized according to General Scheme 5, using benzylamine. ¹H NMR(DMSO-d₆, 400 mHz): δ 12.80 (s; 1H); 9.30 (t; J=5.94 Hz; 1H); 8.55 (d;J=7.09 Hz; 1H); 8.26 (s; 1H); 8.09 (d; J=1.52 Hz; 1H); 7.97 (dd; J=7.93;1.56 Hz; 1H); 7.68 (d; J=7.91 Hz; 1H); 7.59 (s; 1H); 7.34-7.35 (m; 4H);7.25-7.28 (m; 1H); 4.66 (t; J=5.58 Hz; 1H); 4.52 (d; J=5.87 Hz; 2H);4.16 (d; J=9.29 Hz; 2H); 3.36-3.44 (m; 3H); 3.13 (t; J=11.36 Hz; 1H);2.17-2.21 (m; 1H); 1.76-1.80 (m; 1H); 1.56-1.60 (m; 1H); 1.35-1.41 (m;1H). LCMS [M+H]⁺: 520.2.

Example 173: Synthesis of3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide(I-619)

3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamidewas synthesized according to General Scheme 5, using1-methyl-1H-pyrazol-4-amine. ¹H NMR (DMSO-d₆, 400 mHz): δ 10.67 (s; 1H);8.56 (d; J=7.08 Hz; 1H); 8.26 (s; 1H); 8.14 (d; J=1.56 Hz; 1H); 8.07 (s;1H); 8.02 (dd; J=7.93; 1.59 Hz; 1H); 7.73 (d; J=7.93 Hz; 1H); 7.60 (s;2H); 4.66 (t; J=5.47 Hz; 1H); 4.15-4.19 (m; 2H); 3.84 (s; 3H); 3.35-3.43(m; 3H); 3.10-3.17 (m; 1H); 2.17-2.22 (m; 1H); 1.76-1.81 (m; 1H);1.55-1.61 (m; 1H); 1.36-1.43 (m; 1H), NH of indole not observed. LCMS[M+H]⁺: 510.2.

Example 174: Synthesis of3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide(I-246)

3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamidewas synthesized according to General Scheme 5, using pyridine-4-amine.¹H NMR (DMSO-d₆, 400 mHz): δ 10.83 (s; 1H); 8.55 (d; J=7.11 Hz; 1H);8.52 (dd; J=5.29; 1.46 Hz; 2H); 8.26 (s; 1H); 8.18 (d; J=1.57 Hz; 1H);8.04 (dd; J=7.91; 1.60 Hz; 1H); 7.81 (dd; J=5.19; 1.53 Hz; 2H); 7.76 (d;J=7.91 Hz; 1H); 7.57 (s; 1H); 4.15-4.19 (m; 2H); 3.36-3.44 (m; 3H);3.10-3.16 (m; 1H); 2.18-2.22 (m; 1H); 1.77-1.81 (m; 1H); 1.56-1.60 (m;1H); 1.37-1.43 (m; 1H). NH of indole and OH not observed. Containedformic acid at 8.38 ppm (0.4 eq.). LCMS [M+H]⁺: 507.2.

Example 175: Synthesis of(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1-yl)methanone(I-620)

(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1-yl)methanonewas synthesized according to General Scheme 5, using 1-methylpiperazine.¹H NMR (DMSO-d₆, 400 mHz): δ 12.79 (s; 1H); 8.56 (d; J=7.10 Hz; 1H);8.26 (s; 1H); 7.67 (s; 1H); 7.58-7.61 (m; 2H); 7.43 (dd; J=7.73; 1.47Hz; 1H); 4.65 (t; J=5.58 Hz; 1H); 4.12-4.17 (m; 2H); 3.56-3.66 (m; 2H);3.33-3.45 (m; 5H); 3.13 (t; J=11.35 Hz; 1H); 2.28-2.39 (m; 4H); 2.21 (s;3H); 2.17-2.19 (m; 1H); 1.77-1.80 (m; 1H); 1.56-1.60 (m; 1H); 1.36-1.42(m; 1H). LCMS [M+H]⁺: 514.3.

Example 176: Synthesis of3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)benzamide(I-621)

3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)benzamidewas synthesized according to General Scheme 5, using2-oxa-6-azaspiro[3.3]heptane. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.78 (s;1H); 8.81 (d; J=7.16 Hz; 1H); 8.55 (d; J=7.05 Hz; 1H); 8.26 (s; 1H);8.02 (d; J=1.52 Hz; 1H); 7.90 (dd; J=7.94; 1.56 Hz; 1H); 7.66 (d; J=7.91Hz; 1H); 7.55 (s; 1H); 4.63-4.66 (m; 3H); 4.52 (s; 2H); 4.21-4.27 (m;1H); 4.14-4.18 (m; 2H); 3.33-3.43 (m; 3 H); 3.12 (t; J=11.30 Hz; 1H);2.57-2.62 (m; 2H); 2.26 (t; J=10.09 Hz; 2H); 2.16-2.21 (m; 1H);1.77-1.80 (m; 1H); 1.55-1.59 (m; 1H); 1.36-1.41 (m; 1H). LCMS [M+H]⁺:526.3.

Example 177: Synthesis of(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1-yl)methanone(I-622)

(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1-yl)methanonewas prepared according to General Scheme 5, using 1-methylpiperazine. ¹HNMR (DMSO-d₆, 400 mHz): δ 8.53 (d; J=7.11 Hz; 1H); 8.28 (s; 1.3H); 8.24(s; 1H); 7.65 (d; J=8.84 Hz; 1H); 7.60 (s; 1H); 7.53 (m; 2H); 4.14 (m;2H); 3.57 (br s; 2H); 3.32-3.42 (m; 5H); 3.10 (t; J=11.34 Hz; 1H); 2.29(br s; 6H); 2.16 (s; 3H); 1.77 (d; J=13.06 Hz; 1H); 1.51-1.58 (m; 1H);1.32-1.40 (m; 1H). LCMS [M+H]⁺: 513.3, 515.3.

Example 178: Synthesis of(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)methanone(I-623)

(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)methanonewas prepared according to General Scheme 5, using piperidine. ¹H NMR(DMSO-d₆, 400 mHz): δ 8.55 (d; J=7.12 Hz; 1H); 8.35 (s; 0.3H); 8.25 (s;1H); 7.66 (d; J=8.77 Hz; 1H); 7.59 (s; 1H); 7.52-7.54 (m; 2H); 4.66 (brs; 1H); 4.16 (m; 2H); 3.8 (m, 2H); 3.6 (m, 6H); 3.12 (t; J=11.31 Hz;1H); 2.19 (d; J=11.68 Hz; 1H); 1.78 (d; J=13.20 Hz; 1H); 1.59 (br s;8H). LCMS [M+H]⁺: 498.3, 500.3.

Example 179: Synthesis of4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide (I-624)

4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamidewas prepared according to General Scheme 5, using2-methoxyethan-1-amine. ¹H NMR (DMSO-d₆, 400 mHz): δ 8.67 (s; 1H); 8.56(d; J=7.05 Hz; 1H); 8.35 (s; 0.1H); 8.26 (s; 1H); 8.00-8.02 (m; 2H);7.70 (d; J=9.04 Hz; 1H); 7.61 (s; 1H); 4.66 (s; 1H); 4.16 (m; 2H);3.40-3.44 (m; 5H); 3.35 (m; 2H); 3.25 (s; 3H); 3.12 (t; J=11.56 Hz; 1H);2.19 (s; 1H); 1.79 (d; J=13.13 Hz; 1H); 1.53-1.62 (m; 1H); 1.34-1.43 (m;1H). LCMS [M+H]⁺: 488.2, 490.2.

Example 180: Synthesis of(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone(I-625)

(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanonewas prepared according to General Scheme 5, using1,2,3,4-tetrahydroisoquinoline. ¹H NMR (DMSO-d₆, 400 mHz): δ 8.48 (d;J=7.03 Hz; 1H); 8.26 (s; 1.3H); 7.66 (d; J=8.51 Hz; 1H); 7.58 (m; 3H);7.19 (s; 4H); 4.72 (s; 2H); 4.20 (s; 2H); 3.74 (s; 2H); 3.43 (t; J=6.82Hz; 1H); 3.35 (m; 2H); 3.14 (m; 2H); 2.85 (m; 2H); 2.20 (d; J=11.69 Hz;1H); 1.79 (d; J=13.23 Hz; 1H); 1.52-1.61 (m; 1H); 1.42 (t; J=12.35 Hz;1H). LCMS [M+H]⁺: 546.3, 548.25.

Example 181: Synthesis of4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)benzamide (I-626)

4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)benzamidewas prepared according to General Scheme 5, using2-morpholinoethan-1-amine. ¹H NMR (DMSO-d₆, 400 mHz): δ 8.56 (d; J=6.97Hz; 2H); 8.34 (s; 1H); 8.26 (s; 1.3H); 7.98-8.00 (m; 2H); 7.70 (d;J=8.96 Hz; 1H); 7.60 (s; 1H); 4.16 (d; J=9.22 Hz; 2H); 3.55 (t; J=4.54Hz; 4H); 3.33-3.43 (m; 6H); 3.12 (t; J=11.57 Hz; 1H); 2.44 (t; J=6.91Hz; 2H); 2.39 (m; 4H); 2.19 (d; J=11.85 Hz; 1H); 1.79 (d; J=13.00 Hz;1H); 1.53-1.59 (m; 1H); 1.34-1.40 (m; 1H). LCMS [M+H]⁺: 543.3, 545.3.

Example 182: Synthesis of(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone(I-627)

(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanonewas prepared according to General Scheme 5, using1-(pyridin-2-yl)piperazine. ¹H NMR (DMSO-d₆, 400 mHz): δ 8.55 (d; J=7.05Hz; 1H); 8.34 (s; 0.4H); 8.25 (s; 1H); 8.12 (d; J=4.91 Hz; 1H);7.52-7.69 (m; 5H); 6.84 (d; J=8.62 Hz; 1H); 6.66 (dd; J=7.09; 4.93 Hz;1H); 4.15 (d; J=9.32 Hz; 2H); 3.34-3.57 (br m; 12H); 3.12 (t; J=11.30Hz; 1H); 2.19 (d; J=11.63 Hz; 1H); 1.78 (d; J=13.12 Hz; 1H); 1.52-1.61(m; 1H); 1.33-1.42 (m; 1H). LCMS [M+H]⁺: 576.3, 578.3.

Example 183: Synthesis ofN-benzyl-4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide(I-628)

N-Benzyl-4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamidewas prepared according to General Scheme 5, using benzylamine. ¹H NMR(DMSO-d₆, 400 mHz): δ 9.17 (t; J=5.91 Hz; 1H); 8.56 (d; J=7.05 Hz; 1H);8.32 (s; 0.2H); 8.25 (s; 1H); 8.03-8.05 (m; 2H); 7.72 (d; J=8.45 Hz;1H); 7.63 (s; 1H); 7.31 (d; J=4.43 Hz; 4H); 7.24 (d; J=5.57 Hz; 1H);4.66 (br s; 1H); 4.47 (d; J=5.85 Hz; 2H); 4.15 (d; J=9.12 Hz; 2H);3.33-3.41 (m; 3H); 3.12 (t; J=11.58 Hz; 1H); 2.19 (d; J=11.63 Hz; 1H);1.78 (d; J=13.16 Hz; 1H); 1.56 (dd; J=14.28; 11.21 Hz; 1H); 1.34-1.40(m; 1H). LCMS [M+H]⁺: 520.2, 523.3.

Example 184: Synthesis of4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide(I-629)

4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamidewas prepared according to General Scheme 5, using1-methyl-1H-pyrazol-4-amine. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.85 (br s;1H); 10.52 (s; 1H); 8.58 (d; J=7.03 Hz; 1H); 8.37 (s; 0.1H); 8.26 (s;1H); 8.08-8.11 (m; 2H); 8.02 (s; 1H); 7.76 (d; J=8.20 Hz; 1H); 7.65 (s;1H); 7.54 (s; 1H); 4.66 (s; 1H); 4.17 (d; J=9.13 Hz; 2H); 3.82 (s; 3H);3.32-3.41 (m; 3H); 3.13 (t; J=11.60 Hz; 1H); 2.20 (d; J=11.64 Hz; 1H);1.79 (d; J=13.12 Hz; 1H); 1.53-1.62 (m; 1H); 1.39-1.41 (br m; 1H). LCMS[M+H]⁺: 510.2, 512.2.

Example 185: Synthesis of4-chloro-N-(3-cyanophenyl)-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide(I-630)

4-Chloro-N-(3-cyanophenyl)-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamidewas prepared according to General Scheme 5, using 3-aminobenzonitrile.¹H NMR (DMSO-d₆, 400 mHz): δ 10.61 (s; 1H); 8.58 (d; J=7.05 Hz; 1H);8.39 (s; 0.2H); 8.24 (m; 2H); 8.10-8.17 (m; 2H); 8.01-8.04 (m; 1H); 7.80(m; 1H); 7.65 (s; 1H); 7.58 (m; 2H); 4.66 (s; 1H); 4.17 (d; J=9.29 Hz;2H); 3.36-3.42 (m; 3H); 3.13 (t; J=11.56 Hz; 1H); 2.20 (d; J=11.65 Hz;1H); 1.79 (d; J=13.07 Hz; 1H); 1.53-1.62 (m; 1H); 1.34-1.43 (m; 1H).LCMS [M+H]⁺: 531.2, 533.2.

Example 186: Synthesis of4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide(I-631)

4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamidewas prepared according to General Scheme 5, using aniline. ¹H NMR(DMSO-d₆, 400 mHz): δ 10.31 (s; 1H); 8.59 (d; J=7.06 Hz; 1H); 8.41 (s;0.2H); 8.26 (s; 1H); 8.09-8.16 (m; 2H); 7.76 (m; 3H); 7.64 (s; 1H); 7.35(m; 2H); 7.11 (t; J=7.39 Hz; 1H); 4.66 (s; 1H); 4.17 (m; 2H); 3.33-3.41(m; 3H); 3.13 (t; J=11.53 Hz; 1H); 2.20 (d; J=11.72 Hz; 1H); 1.79 (d;J=11.57 Hz; 1H); 1.53-1.62 (m; 1H); 1.39 (q; J=12.08 Hz; 1H). LCMS[M+H]⁺: 506.2, 508.2.

General Procedure I

General procedure for the saponification of a benzoic ester

The benzoic ester substrate (17-A) (1 eq.) were suspended in THF (1mL/0.2 mmol) and methanol (1 mL/0.2 mmol). A solution of 1N lithiumhydroxide was then added (2 eq.) and left to stir at room temperatureovernight. The reaction crude was neutralized with a 1N aqueous solutionof HCl and was concentrated to dryness. The crude product was used as iswithout further purification.

Example 187: Synthesis of(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(morpholine-4-carbonyl)phenyl)methanone (I-632)

(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(morpholine-4-carbonyl)phenyl)methanonewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 12.74 (s; 1H); 8.66 (d; J=7.13 Hz; 1H); 8.25 (s; 1H); 7.81-7.83(m; 3H); 7.55 (d; J=7.88 Hz; 2H); 4.65 (t; J=5.51 Hz; 1H); 4.12-4.17 (m;2H); 3.55-3.68 (m; 7H); 3.35-3.45 (m; 5H); 3.11 (t; J=11.26 Hz; 1H);2.15-2.20 (m; 1H); 1.77-1.80 (m; 1H); 1.53-1.59 (m; 1H); 1.36-1.42 (m;1H). LCMS [M+H]⁺: 466.1.

Example 188: Synthesis of4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide(I-633)

4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamidewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 12.76 (br s; 1H); 10.62 (s; 1H); 8.69 (d; J=7.17 Hz; 1H); 8.25(s; 1H); 8.17 (s; 1H); 8.09 (d; J=8.10 Hz; 2H); 8.07 (s; 1H); 7.90 (d;J=8.09 Hz; 2H); 7.79 (s; 1H); 7.60 (s; 1H); 4.65 (s; 1H); 4.11-4.21 (m;2H); 3.84 (s; 3H); 3.38-3.45 (m; 1H); 3.30-3.35 (m; 6H); 3.12 (t;J=11.19 Hz; 1H); 2.13-2.23 (m; 1H); 1.74-1.82 (m; 1H); 1.51-1.63 (m;1H); 1.31-1.44 (m; 1H). LCMS [M+H]⁺: 476.2.

Example 189: Synthesis of3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide(I-634)

3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamidewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 12.76 (s; 1H); 10.37 (s; 1H); 8.70 (d; J=7.11 Hz; 1H); 8.35 (s;1H); 8.26 (s; 1H); 8.20 (d; J=7.86 Hz; 1H); 7.99 (d; J=7.69 Hz; 1H);7.89 (s; 1H); 7.78 (d; J=8.06 Hz; 2H); 7.71 (t; J=7.73 Hz; 1H); 7.36 (t;J=7.79 Hz; 2H); 7.12 (t; J=7.39 Hz; 1H); 4.13-4.19 (m; 2H); 3.29-3.45(m; 5H); 3.12 (t; J=11.03 Hz; 1H); 2.16-2.21 (m; 1H); 1.76-1.81 (m; 1H);1.52-1.59 (m; 1H); 1.34-1.43 (m; 1H). LCMS [M+H]⁺: 472.2.

Example 190: Synthesis of(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-(morpholine-4-carbonyl)phenyl)methanone (I-635)

(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-(morpholine-4-carbonyl)phenyl)methanonewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 12.72 (s; 1H); 8.65 (d; J=7.24 Hz; 1H); 8.26 (s; 1H); 7.86 (dt;J=7.46; 1.57 Hz; 1H); 7.78 (s; 1H); 7.76 (t; J=1.65 Hz; 1H); 7.68 (dt;J=7.65; 1.51 Hz; 1H); 7.63 (t; J=7.54 Hz; 1H); 4.67 (t; J=5.53 Hz; 1H);4.13-4.21 (m; 2H); 3.50-3.71 (m; 7H); 3.35-3.49 (m; 5H); 3.12 (t;J=11.32 Hz; 1H); 2.16-2.23 (m; 1H); 1.77-1.83 (m; 1H); 1.51-1.63 (m;1H); 1.35-1.45 (m; 1H). LCMS [M+H]⁺: 466.2.

Example 191: Synthesis of4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide(I-636)

4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamidewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 8.67-8.72 (m; 2H); 8.24 (s; 1H); 7.98-8.00 (m; 2H); 7.82-7.84(m; 2H); 7.76 (s; 1H); 4.65 (t; J=5.48 Hz; 1H); 4.11-4.17 (m; 2H);3.58-3.61 (m; 1H); 3.38-3.50 (m; 6H); 3.28 (s; 3H); 3.11 (t; J=11.28 Hz;1H); 2.15-2.21 (m; 1H); 1.75-1.81 (m; 2H); 1.54-1.61 (m; 1H); 1.33-1.43(m; 1H). LCMS [M+H]⁺: 454.2.

Example 192: Synthesis of3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide(I-637)

3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamidewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 12.73 (br s; 1H); 8.66-8.71 (m; 2H); 8.25 (s; 1H); 8.22-8.23 (m;1H); 8.08-8.11 (m; 1H); 7.91-7.93 (m; 1H); 7.80 (s; 1H); 7.63 (t; J=7.73Hz; 1H); 4.65 (t; J=5.55 Hz; 1H); 4.11-4.18 (m; 2H); 3.37-3.49 (m; 8H);3.27 (s; 3H); 3.11 (t; J=11.22 Hz; 1H); 2.14-2.22 (m; 1H); 1.74-1.82 (m;1H); 1.51-1.61 (m; 1H); 1.32-1.44 (m; 1H). LCMS [M+H]⁺: 454.2.

Example 193: Synthesis of3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide(I-638)

3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamidewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 12.76 (s; 1H); 10.56 (s; 1H); 8.68 (d; J=7.22 Hz; 1H); 8.34 (t;J=1.66 Hz; 1H); 8.24-8.25 (m; 1H); 8.20 (dt; J=7.82; 1.40 Hz; 1H); 8.05(s; 1H); 7.96 (dt; J=7.69; 1.35 Hz; 1H); 7.86 (s; 1H); 7.69 (t; J=7.74Hz; 1H); 7.58 (d; J=0.72 Hz; 1H); 4.66 (t; J=5.45 Hz; 1H); 4.13-4.21 (m;3H); 3.83 (s; 3H); 3.38-3.45 (m; 2H); 3.34-3.37 (m; 3H); 3.11 (t;J=11.07 Hz; 2H); 2.16-2.19 (m; 2H); 1.77-1.80 (m; 2H); 1.52-1.62 (m;2H); 1.34-1.44 (m; 2H). LCMS [M+H]⁺: 476.2.

Example 194: Synthesis of4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide(I-231)

4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamidewas synthesized according to General Scheme 6. ¹H NMR (DMSO-d₆, 400mHz): δ 12.80 (s; 1H); 10.46 (s; 1H); 8.74 (d; J=7.15 Hz; 1H); 8.30 (s;1H); 8.15 (d; J=8.03 Hz; 2H); 7.95 (d; J=8.03 Hz; 2H); 7.86 (s; 1H);7.83 (d; J=5.06 Hz; 2H); 7.42 (t; J=7.77 Hz; 2H); 7.17 (t; J=7.37 Hz;1H); 4.70 (t; J=5.53 Hz; 1H); 4.16-4.23 (m; 2H); 3.42-3.47 (m; 1H);3.37-3.41 (m; 2H); 3.16 (t; J=11.18 Hz; 1H); 2.19-2.25 (m; 1H);1.81-1.85 (m; 1H); 1.60-1.66 (m; 1H); 1.38-1.47 (m; 1H). LCMS [M+H]⁺:472.2.

Example 195: Synthesis ofN-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide(I-276) Step 1: Synthesis of(2-chloro-4-nitrophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

(2-Chloro-4-nitrophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas synthesized according General Procedure A, step 1, using4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 2-chloro-4-nitrobenzoylchloride. LCMS [M+H]: 337.9.

Step 2: Synthesis of(2-chloro-4-nitrophenyl)(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

Protection of the nitrogen was achieved according to General ProcedureA, step 1 LCMS [M+H]⁺: 467.0.

Step 2: Synthesis of(2-chloro-4-nitrophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

The chloride displacement was done according to General Procedure A,step 2, with ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. LCMS[M+H]⁺: 562.2

Step 3: Synthesis of(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-nitrophenyl)methanone

To a solution of (2-chloro-4-nitrophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrol[2,3-d]pyrimidin-5-yl)methanone(1260 mg, 2.242 mmol) in DMF (12 mL) were added TBDMS-C₁ (405 mg, 2.69mmol) and imidazole (305 mg, 4.483 mmol). The reaction mixture wasstirred at room temperature for 18 hours. The reaction mixture wasdiluted with EtOAc (50 mL) and aqueous saturated NH₄Cl (60 mL). Thelayers were partitioned and the aqueous layer was extracted with EtOAc(40 mL). The combined organic layers were washed with aqueous saturatedNaHCO₃(60 mL), water (60 mL) and brine. The n it was dried over MgSO₄,filtered and concentrated to dryness to afford 1600 mg of the desiredmaterial which was used in the subsequent step without furtherpurification.

Step 4: Synthesis of(4-Amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl) oxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

Sylilation was achieved under standard conditions. LCMS [M+H]: 646.4.

General Procedure J

A General Method for Amide Formation Using an Acyl Chloride withSilyl-Protected Aniline Substrate Followed by Desilylation

A solution of(4-amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(23-A) (1 eq) in DCM (1 mL/0.05 mmol) is treated with corresponding acylchloride (1.5 eq) and triethylamine (3 eq) at room temperature for 3h.The mixture is then concentrated and 4M HCl in dioxane (2 mL/0.05 mmol)is added. The mixture is stirred at 40° C. overnight then concentratedand the residue purified by preparative reverse phase HPLC (gradientfrom 30% to 95% of acetonitrile+0.1% formic acid).

Step 5: Synthesis ofN-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide(I-276)

N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamidewas synthesized according to General Scheme 7, using benzoyl chloride.¹H NMR (DMSO-d₆, 400 MHz): δ 12.90 (bs, 1H), 10.62 (s, 1), 8.85 (bs,1H), 8.29 (s, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.87 (dd,J=8.4 Hz, J=1.8 Hz, 1H), 7.65-7.55 (m, 5H), 4.18-4.10 (m, 2H), 3.45-3.33(m, 3H), 3.18-3.13 (m, 1H), 2.22-2.19 (m, 1H), 1.81-1.75 (m, 1H),1.66-1.56 (m, 1H), 1.44-1.34 (m, 1H). LCMS [M+H]⁺: 506.2.

Example 196: Synthesis ofN-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide(I-639)

N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamidewas synthesized according to General Scheme 7, using 2-phenylacetylchloride. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.70 (bs, 1H), 10.63 (s, 1H),8.60 (d, J=7.2 Hz, 1H), 8.23 (s, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.59 (dd,J=8.4 Hz, J=1.8 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.35-7.32(m, 3H), 7.28-7.25 (m, 1H), 4.66 (bs, 1H), 4.19-4.10 (m, 2H), 3.70 (s,2H), 3.43-3.40 (m, 1H), 3.45-3.31 (m, 3H), 3.14-3.08 (m, 1H), 2.19-2.16(m, 1H), 1.79-1.76 (m, 1H), 1.62-1.52 (m, 1H), 1.43-1.32 (m, 1H). LCMS[M+H]⁺: 520.1.

Example 197: Synthesis ofN-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropane-1-carboxamide(I-640)

N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropane-1-carboxamidewas synthesized according to General Scheme 7, using1-phenylcyclopropane-1-carbonyl chloride.

¹H NMR (DMSO-d₆, 400 mHz): δ 9.58 (s, 1H), 8.60 (d, J=7.0 Hz, 1H), 8.22(s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.65 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.51(s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.42-7.35 (m, 4H), 7.32-7.28 (m, 1H),4.65 (bs, 1H), 4.18-4.10 (m, 2H), 3.44-3.33 (m, 7H) 3.14-3.08 (m, 1H),2.19-2.16 (m, 1H), 1.79-1.76 (m, 1H), 1.62-1.52 (m, 1H), 1.48 (dd, J=6.8Hz, J=4.5 Hz, 2H), 1.42-1.32 (m, 1H), 1.16 (dd, J=6.8 Hz, J=4.5 Hz, 2H).LCMS [M+H]⁺: 546.3.

Example 198: Synthesis of2-(benzyloxy)-N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)acetamide (I-641)

2-(Benzyloxy)-N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)acetamidewas synthesized according to General Scheme 7, using 2-(benzyloxy)acetylchloride. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.73 (bs, 1H), 10.24 (s, 1H),8.62 (d, J=7.0 Hz, 1H), 8.24 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.70 (dd,J=8.4 Hz, J=1.8 Hz, 1H), 7.55 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.43-7.37(m, 3H), 7.34-7.31 (m, 1H), 4.64 (s, 2H), 4.15 (bs, 4H), 4.06-3.88 (m,1H), 3.57-3.51 (m, 3H), 3.46-3.33 (m, 11H+H₂O), 3.15-3.09 (m, 1H),2.20-2.17 (m, 1H), 1.91-1.80 (m, 1H), 1.63-1.50 (m, 1H), 1.44-1.31 (m,1H). LCMS [M+H]⁺: 550.2.

Example 199: Synthesis ofN-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide(I-642)

N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamidewas prepared according to General Scheme 8 and using benzoic acid. ¹HNMR (DMSO-d₆, 400 mHz): d 12.71 (s; 1H); 10.45 (s; 1H); 8.72 (d; J 6.93Hz; 1H); 8.23 (s; 2H); 8.03 (d; J 6.49 Hz; 1H); 7.97 (d; J 7.51 Hz; 2H);7.83 (s; 1H); 7.51-7.60 (m; 5H); 4.64 (t; J 5.34 Hz; 1H); 4.14 (d; J9.29 Hz; 2H); 3.35-3.43 (m; 3H); 3.11 (t; J 11.33 Hz; 1H); 2.15-2.18 (m;1H); 1.75-1.78 (m; 1H); 1.52-1.61 (m; 1H); 1.32-1.41 (m; 1H). LCMS[M+H]⁺: 472.2.

Example 200: Synthesis ofN-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)picolinamide(I-643)

N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)picolinamidewas prepared according to General Scheme 8 and using 2-picolinic acid.¹H NMR (DMSO-d₆, 400 mHz): δ 12.75 (s; 1H); 10.94 (s; 1H); 8.77 (m; 2H);8.38 (s; 1H); 8.25 (s; 1H); 8.15-8.19 (m; 3H); 8.07-8.11 (m; 1H); 7.89(s; 1H); 7.68-7.71 (m; 1H); 7.54 (m; 2H); 4.15 (d; J 9.34 Hz; 2H); 3.13(t; J 11.53 Hz; 1H); 2.18 (s; 1H); 1.78 (d; J 13.08 Hz; 1H); 1.59 (d;J=12.82 Hz; 1H); 1.39 (d; J 12.79 Hz; 1H). LCMS [M+H]⁺: 472.1.

Example 201: Synthesis ofN-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4-carboxamide(I-644)

N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4-carboxamidewas prepared according to General Scheme 8 and usingtetrahydro-2H-pyran-4-carboxylic acid. ¹H NMR (DMSO-d₆, 400 mHz): δ12.70 (s; 1H); 10.12 (s; 1H); 8.70 (d; J=7.05 Hz; 1H); 8.24 (s; 1H);8.08 (s; 1H); 7.78-7.81 (m; 2H); 7.45-7.49 (m; 2H); 4.65 (t; J=5.56 Hz;1H); 4.14 (d; J=9.28 Hz; 2H); 3.91 (d; J=11.26 Hz; 2H); 3.11 (t; J=11.56Hz; 1H); 2.60 (s; 1H); 2.17 (s; 1H); 1.65-1.71 (m; 4H); 1.40 (s; 1H).LCMS [M+H]⁺: 480.3.

Example 202: Synthesis ofN-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-methoxyacetamide(I-645)

N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-methoxyacetamidewas prepared according to General Scheme 8 and using 2-methoxyaceticacid. ¹H NMR (DMSO-d₆, 400 mHz): δ 12.71 (s; 1H); 10.01 (s; 1H); 8.71(d; J=7.08 Hz; 1H); 8.24 (s; 1H); 8.13 (s; 1H); 7.89-7.92 (m; 1H); 7.80(s; 1H); 7.48 (m; 2H); 4.65 (t; J=5.58 Hz; 1H); 4.14 (m; 2H); 4.03 (s;2H); 3.11 (t; J=11.53 Hz; 1H); 2.17 (m; 1H); 1.78 (m; 1H); 1.57 (m; 1H);1.33-1.43 (m; 1H). LCMS [M+H]⁺: 440.2.

General Procedure K A General Procedure for Arylamine Formation

The arylfluoride substrate (26-A) (1 eq.) was diluted in NMP (1 mL/1.32mmol). Cyclic amine (1.1 eq.) and potassium carbonate (2 eq.) were addedand the mixture was stirred at 120° C. overnight. The reaction mixturewas allowed to cool to room temperature and was diluted with water. Thecrude mixture was extracted with ethyl acetate (×3) and the combinedorganics were washed with water (×2). Organics were dried over magnesiumsulfate, filtered and concentrated to dryness. The product was purifiedby silica gel chromatography (0-50% ethyl acetate in hexanes).

General Procedure L A General Procedure for Phenol Alkylation

A mixture of phenol (26-B) (1 eq.), 1-chloro-2-methoxyethane (1.5 eq.),potassium carbonate (2 eq.) and sodium iodide (0.2 eq.) in DMF (1mL/0.45 mmol) is heated overnight at 80° C. The reaction mixture is thencooled to room temperature and poured in water, stirred for 15 min andfiltered then dried under high vacuum. The product was used as iswithout further purification.

General Procedure M A General Procedure for Ketone Formation ThroughAryllithium Attack on an Ester

5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3-A) (1 eq.) was dilutedin dry THF (1 mL/0.21 mmol) and was cooled to −78° C. n-BuLi (2.1 eq.)was added dropwise and the temperature was monitored with an internalthermocouple to ensure the reaction temperature never rose above −60° C.The reaction mixture was stirred for 1 hour before the substitutedmethyl benzoate (27-A/B) (1.05 eq.) in dry THF (1 mL/0.9 mmol) was addeddropwise with the internal temperature never exceeding −60° C. Themixture was stirred at −78° C. for 1 hour then quenched with saturatedaqueous Ammonium chloride solution and extracted with ethyl acetate(×3). The combined organic layers were washed with sodium bicarbonateand dried over magnesium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel column chromatography(10-100% ethyl acetate in hexanes).

Example 203: Synthesis of(2-chloro-4-morpholinophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-311i)

(2-Chloro-4-morpholinophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas synthesized according to General Scheme 9, using((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. ¹H NMR (DMSO-d₆, 400mHz): δ 12.61 (s; 1H); 8.65 (d; J=6.98 Hz; 1H); 8.23 (s; 1H); 7.50 (s;1H); 7.43 (d; J=8.54 Hz; 1H); 7.07 (s; 1H); 6.96 (d; J=8.68 Hz; 1H);4.65 (t; J=5.29 Hz; 1H); 4.10-4.15 (m; 2H); 3.73-3.75 (m; 4H); 3.38-3.43(m; 3H); 3.26-3.27 (m; 4H); 3.11 (t; J=11.29 Hz; 1H); 2.15-2.20 (m; 1H);1.76-1.79 (m; 1H); 1.49-1.60 (m; 1H); 1.33-1.43 (m; 1H). LCMS [M+H]⁺:472.

Example 204: Synthesis of(2-chloro-4-(piperidin-1-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-646)

(2-Chloro-4-(piperidin-1-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas synthesized according to General Scheme 9, using((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. ¹H NMR (DMSO-d₆, 400mHz): δ 12.60 (s; 1H); 8.66 (d; J=7.11 Hz; 1H); 8.22 (s; 1H); 7.51 (s;1H); 7.38 (d; J=8.66 Hz; 1H); 7.01 (d; J=2.36 Hz; 1H); 6.91 (dd; J=8.75;2.40 Hz; 1H); 4.66 (t; J=5.54 Hz; 1H); 4.12-4.18 (m; 2H); 3.36-3.42 (m;3H); 3.30-3.32 (m; 4H); 3.11 (t; J=11.42 Hz; 1H); 2.16-2.20 (m; 1H);1.74-1.79 (m; 1H); 1.51-1.58 (m; 8H); 1.33-1.43 (m; 1H). LCMS [M+H]⁺:470.

Example 205: Synthesis of(2-chloro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-647)

(2-Chloro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas synthesized according to General Scheme 9, using2-oxa-6-azaspiro[3.3]heptane, and((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. ¹H NMR (DMSO-d₆, 400mHz): δ 12.59 (s; 1H); 8.65 (d; J=7.08 Hz; 1H); 8.22 (s; 1H); 7.44 (s;1H); 7.39 (d; J=8.37 Hz; 1H); 6.54 (d; J=2.18 Hz; 1H); 6.41 (dd; J=8.42;2.21 Hz; 1H); 4.73 (s; 4H); 4.65 (t; J=5.57 Hz; 1H); 4.11-4.17 (m; 2H);4.10 (s; 4H); 3.35-3.44 (m; 3H); 3.10 (t; J=11.53 Hz; 1H); 2.15-2.19 (m;1H); 1.76-1.80 (m; 1H); 1.51-1.61 (m; 1H); 1.32-1.42 (m; 1H). LCMS[M+H]⁺: 484.

Example 206: Synthesis of(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(2-methoxyethoxy)phenyl)methanone(I-318i)

(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(2-methoxyethoxy)phenyl)methanonewas prepared according to General Scheme 9, using methyl4-hydroxybenzoate and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol.¹H NMR (DMSO-d₆, 400 mHz): δ 12.63 (bs, 1H), 8.66 (d, J=7.2 Hz, 1H),8.23 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.76 (s, 1H), 7.08 (d, J=8.8 Hz,2H), 4.65 (bs, 1H), 4.22-4.19 (m, 2H), 4.16-4.11 (m, 2H), 3.71-3.69 (m,2H), 3.42-3.39 (m, 1H), 3.36-3.30 (m, 4H+H₂O), 3.13-3.07 (m, 1H),2.18-2.15 (m, 1H), 1.79-1.76 (m, 1H), 1.61-1.51 (m, 1H), 1.42-1.32 (m,1H). LCMS [M+H⁺]: 427.30.

Example 207: Synthesis of(2-chloro-4-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-317i)

(2-Chloro-4-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Scheme 9, using methyl2-chloro-4-hydroxybenzoate and((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. ¹H NMR (DMSO-d₆, 400mHz): δ 12.70 (bs, 1H), 8.61 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 7.48 (s,1H), 7.47 (d, J=8.6 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.00 (dd, J=8.4,2.3 Hz, 1H), 4.45 (bs, 1H), 4.20-4.17 (m, 2H), 4.17-4.11 (m, 2H),3.68-3.65 (m, 2H), 3.48-3.33 (m, 3H), 3.30 (m, 3H), 3.13-3.07 (m, 1H),2.18-2.15 (m, 1H), 1.79-1.76 (m, 1H), 1.60-1.50 (m, 1H), 1.40-1.34 (m,1H). Presence of formic acid at 8.42 mm (0.2 equivalents). LCMS [M+H⁺]:461.20.

Example 208: Synthesis of(2-chloro-5-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-648)

(2-Chloro-5-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Scheme 9, using methyl methyl2-chloro-5-hydroxybenzoate and((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. ¹H NMR (DMSO-d₆, 400mHz): δ 12.73 (bs, 1H), 8.57 (d, J=7.4 Hz, 1H), 8.23 (s, 1H), 7.51 (s,1H), 7.44 (d, J=8.6 Hz, 1H), 7.12-7.07 (m, 2H), 4.64 (bs, 1H), 4.15-4.10(m, 4H), 3.63-3.61 (m, 2H), 3.45-3.31 (m, 3H), 3.27 (m, 3H), 3.12-3.07(m, 1H), 2.18-2.15 (m, 1H), 1.78-1.74 (m, 1H), 1.60-1.51 (m, 1H),1.41-1.32 (m, 1H). Presence of formic acid at 8.37 ppm (0.08equivalents). LCMS [M+H^(+]): 461.20.

Example 209: Synthesis of(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-(2-methoxyethoxy)phenyl)methanone(I-649)

(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-(2-methoxyethoxy)phenyl)methanonewas prepared according to General Scheme 9, using methyl3-hydroxybenzoate and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol.¹H NMR (DMSO-d₆, 400 mHz): δ 12.67 (bs, 1H), 8.68 (d, J=7.2 Hz, 1H),8.24 (s, 1H), 7.77 (s, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz,1H), 7.28 (m, 1H), 7.20 (dd, J=8.2 Hz, J=2.0 Hz, 1H), 4.65 (bs, 1H),4.19-4.11 (m, 4H), 3.69-3.67 (m, 2H), 3.44-3.40 (m, 1H), 3.35-3.27 (m,6H), 3.13-3.08 (m, 1H), 2.19-2.16 (m, 1H), 1.79-1.76 (m, 1H), 1.61-1.51(m, 1H), 1.44-1.33 (m, 1H). Presence of formic acid at 8.37 ppm (0.1equivalents). LCMS [M+H⁺]: 427.20.

Example 210: Synthesis of(2-chloro-4-(phenylamino)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-650) Step 1: Synthesis of(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-(phenylamino)phenyl)methanoneand(2-chloro-4-(phenylamino)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

(4-Amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)-ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(200 mg, 0.309 mmol) was dissolved in dioxane (2 mL). Bromobenzene (36μL, 0.34 mmol) and sodium tert-butoxide (42 mg, 0.43 mmol) were added.The crude was degassed with argon and Pd₂(dba)₃ (6 mg, 0.006 mmol) andBINAP (14 mg, 0.022 mmol) were added. The reaction was then capped andheated to 100° C. for 3 hours. After cooling to room temperature thecrude was diluted in water and ethyl acetate. The biphasic mixture wasextracted with ethyl acetate (×2). The combined organics were dried overMgSO₄, filtered and concentrated. The residue was purified by silica gelcolumn chromatography eluting a gradient of 0% to 100% ethyl acetate inhexanes. Combined both products to get 150 mg of yellow oil.

Step 2: Synthesis of(2-Chloro-4-(phenylamino)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-650)

Deprotection of the silyl groups was achieved using General Procedure H.¹H NMR (DMSO-d₆, 400 mHz): δ 12.64 (s; 1H); 8.75 (s; 1H); 8.66 (d;J=7.13 Hz; 1H); 8.23 (s; 1H); 7.59 (s; 1H); 7.43 (d; J=8.43 Hz; 1H);7.32-7.37 (m; 2H); 7.20 (dd; J=7.97; 1.21 Hz; 2H); 7.09 (d; J=2.16 Hz;1H); 6.99-7.04 (m; 2H); 4.65 (t; J=5.58 Hz; 1H); 4.08-4.17 (m; 2H);3.39-3.45 (m; 1H); 3.34-3.38 (m; 2H); 3.11 (t; J=11.42 Hz; 1H);2.16-2.20 (m; 1H); 1.76-1.80 (m; 1H); 1.52-1.62 (m; 1H); 1.33-1.43 (m;1H). LCMS [M+H]⁺: 478.

General Procedure N

One general procedure for formation of a diaryl ether is described.

Fluoropyridine substrate (29-B) (1 eq.), methyl-hydroxy-benzoate (29-A)(1 eq.) and potassium carbonate (1 eq.) were dissolved in DMSO (1 mL/0.3mmol). The mixture was stirred at 120° C. under argon atmosphereovernight. After cooled, the reaction mixture was diluted in water andextracted several times with ethyl acetate. Combined organics werewashed with water and dried over magnesium sulfate and concentratedunder reduced pressure. The product was purified by columnchromatography (0-100% ethyl acetate in hexanes).

Example 211: Synthesis of6-(4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamide(I-320)

6-(4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamidewas synthesized according to General Scheme 11, using6-fluoro-N-methylpicolinamide and methyl-4-hydroxy-benzoate. ¹H NMR(DMSO-d₆, 400 mHz): δ 8.61 (d; J=7.13 Hz; 1H); 8.15-8.17 (m; 2H); 8.02(dd; J=8.22; 7.41 Hz; 1H); 7.78-7.82 (m; 4H); 7.22 (t; J=8.83 Hz; 3H);4.53-4.66 (m; 1 H); 4.06-4.12 (m; 2H); 3.32-3.42 (m; 3H); 3.04 (t;J=11.35 Hz; 1H); 2.72 (d; J=4.81 Hz; 3H); 2.08-2.13 (m; 1H); LCMS [M+H]:503.1.

Example 212: Synthesis of6-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamide (I-319)

6-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamidewas synthesized according to General Scheme 11, using6-fluoro-N-methylpicolinamide and methyl 2-chloro-4-hydroxybenzoate. ¹HNMR (DMSO-d₆, 400 mHz): δ 12.72 (br s; 1H); 8.54 (d; J=7.11 Hz; 1H);8.23 (q; J=4.87 Hz; 1H); 8.19 (s; 1H); 8.03 (dd; J=8.21; 7.43 Hz; 1H);7.79 (dd; J=7.41; 0.80 Hz; 1H); 7.64 (s; 1H); 7.56 (d; J=8.41 Hz; 1H);7.41 (d; J=2.28 Hz; 1H); 7.25 (dd; J=8.19; 0.81 Hz; 1H); 7.18 (dd;J=8.40; 2.30 Hz; 1H); 4.57-4.60 (m; 1H); 4.05-4.12 (m; 2H); 3.27-3.35(m; 3H); 3.06 (t; J=11.29 Hz; 1H); 2.73 (d; J=4.83 Hz; 3H); 2.11-2.14(m; 1H); 1.71-1.74 (m; 1H); 1.45-1.58 (m; 1H); 1.27-1.37 (m; 1H). LCMS[M+H]: 537.2.

Example 213: Synthesis of5-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamide (I-651)

5-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamidewas synthesized according to General Scheme 11, using5-fluoro-N-methylpicolinamide and methyl 2-chloro-4-hydroxybenzoate. ¹HNMR (DMSO-d₆, 400 mHz): δ 12.73 (br s; 1H); 8.62-8.66 (m; 1H); 8.52 (d;J=7.11 Hz; 1H); 8.47 (d; J=2.78 Hz; 1H); 8.19 (s; 1H); 8.01 (d; J=8.64Hz; 1H); 7.66 (dd; J=8.63; 2.81 Hz; 1H); 7.61 (s; 1H); 7.57 (d; J=8.42Hz; 1H); 7.38 (d; J=2.34 Hz; 1H); 7.15 (dd; J=8.42; 2.36 Hz; 1H);4.57-4.60 (m; 1H); 4.03-4.12 (m; 2H); 3.28-3.37 (m; 3H); 3.06 (t;J=11.30 Hz; 1H); 2.76 (d; J=4.81 Hz; 3H); 2.10-2.16 (m; 1H); 1.70-1.73(m; 1H); 1.46-1.56 (m; 1H); 1.26-1.38 (m; 1H). LCMS [M+H]: 537.1.

Example 214: Synthesis ofN-(4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamide(I-652) Step 1: Synthesis of methyl4-((2-methoxybenzamido)methyl)benzoate (652a)

The compound was prepared according to General Procedure F, using methyl4-(aminomethyl)benzoate hydrochloride and 2-methoxybenzoic acid. LCMS[M+H]: 300.1.

Step 2: Synthesis ofN-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamide(652b)

N-(4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamidewas prepared according to General Procedure M, using methyl4-((2-methoxybenzamido)methyl) benzoate and 3-A. After 1 h at −78° C.,the reaction mixture was allowed to warm up to 0° C. over 1 h. LCMS[M+H]: 421.1.

Step 3: Synthesis ofN-(4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamide(I-652)

N-(4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamidewas prepared according to General Scheme 12, General Procedure A, step2, with ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. After removalof solvents, the residue was diluted with EtOAc (30 mL) and water (20mL). The layers were partitioned and the organic layer was washed withwater (20 mL) and brine, dried over MgSO₄, filtered and concentrated todryness. The residue was purified by reverse phase C18 using IscoCombiFlash (30 g column, loaded with DMSO) eluting with 5-80%CH₃CN/water (+0.1% formic acid) over 20 minutes. ¹H NMR (DMSO-d₆, 400mHz): δ 12.66 (s; 1H); 8.80-8.83 (m; 1H); 8.71-8.73 (m; 1H); 8.23 (s;1H); 7.75-7.78 (m; 4H); 7.47-7.51 (m; 3H); 7.17 (d; J=8.35 Hz; 1H);7.03-7.07 (m; 1H); 4.65 (t; J=5.56 Hz; 1H); 4.60 (d; J=6.13 Hz; 2H);4.09-4.18 (m; 2H); 3.92 (s; 3H); 3.26-3.36 (m; 3H); 3.08-3.14 (m; 1H);2.13-2.20 (m; 1H); 1.74-1.81 (m; 1H); 1.50-1.60 (m; 1H); 1.32-1.43 (m;1H). LCMS [M+H]: 516.3.

Step 1: Synthesis of tert-butyl(racemic)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate(37-A)

The intermediate 37-A was prepared according General Procedure A, using3-amino-N-Boc-piperidine and(2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(36-A). LCMS [M+H]⁺: 548.1.

Step 1′: Synthesis of tert-butyl(racemic)-2-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylate(37-B)

The intermediate 37-B was prepared according General Procedure A, usingtert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate and(2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.LCMS [M+H]⁺: 548.1.

General Procedure O

One general procedure for Boc-deprotection is described.

Boc-protected amine (37-A/B) (1.0 equiv) was dissolved in DCM (1.0mL/mmol) and a 4.0M HCl/Dioxane solution (4.0 equiv) was added. Mixturewas stirred at room temperature for 2.0 h, then concentrated undervacuum. A 1:10 solution of aqueous ammonia in EtOH was added untilcomplete dissolution of the residue. The residue was absorbed ontosilica and purified by normal phase column chromatography to give thepurified amine product.

Step 2: Synthesis of(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(38-A)

Intermediate 37-A was BOC-deprotected according to General Scheme 13General Procedure O. LCMS [M+H]⁺: 448.10.

Step 2′: Synthesis of(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(38-B)

Intermediate 37-B was BOC-deprotected according to General Scheme 13General Procedure O. LCMS [M+H]⁺: 448.10.

Example 215: Synthesis of(racemic)-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one(I-324r)

(racemic)-1-(3-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-onewas prepared according to General Scheme 13 and General Scheme 5, step3, using(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneand 2-butynoic acid. ¹H NMR (CDCl₃, 400 mHz, 3:2 amide rotamer/conformerratio, asterisks denote minor rotamer/conformer peaks): δ 9.11 (d, J 7.0Hz, 1H), 9.07* (d, J 7.6 Hz, 1H), 8.37 (s, 1H), 8.30* (s, 1H), 7.41-7.45(m, 3H), 7.37 (d, J 7.6 Hz, 1H), 7.23 (t, J 7.5 Hz, 1H), 7.11 (s, 1H),7.07-7.08 (m, 2H), 6.95-6.99 (m, 1H), 4.24-4.39 (m, 2H), 3.97-4.02* (m,1H), 3.81-3.87 (m, 1H), 3.73 (dd, J 13.0, 7.4 Hz, 1H), 3.41-3.56 (m,1H), 3.34* (dd, J 12.6, 8.0 Hz, 1H), 2.14-2.25 (m, 1H), 1.60-2.10 (m,3H), 2.01* (s, 3H), 1.80 (s, 3H). LCMS [M+H]⁺: 514.10.

Example 216: Synthesis of(racemic)-1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)but-2-yn-1-one(I-328r)

(racemic)-1-(2-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)but-2-yn-1-onewas prepared according to General Scheme 13 and General Scheme 5, step3, using(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneand 2-butynoic acid. ¹H NMR (CDCl₃, 400 mHz, 2:1 amide rotamer ratio,asterisks denote minor rotamer peaks): δ 9.17 (t, J=6.2 Hz, 1H), 9.01*(t, J=5.9 Hz, 1H), 8.34 (s, 1H), 7.34-7.47 (m, 4H), 7.20-7.26 (m, 1H),7.12 (s, 1H), 7.08-7.09 (m, 2H), 6.97 (dd, J=8.4, 2.3 Hz, 1H), 4.40-4.54(m, 1H), 3.98-4.10 (m, 1H), 3.69-3.88 (m, 2H), 3.49-3.66 (m, 1H)1.92-2.17 (4H, m), 1.98* (3H, s), 1.89 (3H, s). LCMS [M+H]⁺: 514.10.

Example 217: Synthesis of(racemic)-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(I-321r)

(racemic)-1-(3-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared according to General Scheme 13 and General Scheme 5, step3, using(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneand acrylic acid. ¹H NMR 400 MHz (DMSO-d6. 3:2 amide rotamer ratio,asterisks denote minor rotamer peaks): δ 12.8 (br s, 1H); 8.85 (d, J=7.3Hz, 1H); 8.27 (br s, 1H); 7.62 (s, 1H); 7.55 (d, J=8.4 Hz, 1H); 7.48 (t,J=7.6 Hz, 2H); 7.25 (t, J=7.3 Hz, 1H); 7.17-7.19 (m, 3H); 7.02 (d, J=8.4Hz, 1H); *6.77-6.84 (m, 1H); 6.56-6.64 (m, 1H); 5.93-6.05 (m, 1H);*5.60-5.65 (m, 1H); 5.46-5.51 (m, 1H); 4.17-4.25 (m, 1H); *4.00-4.06 (m,1H); 3.89-3.95 (m, 1H); 3.45-3.71 (m, 2H); 3.20-3.30 (m, 1H); 2.01-2.10(m, 1H); 1.72-1.85 (m, 2H); 1.53-1.63 (m, 1H). LCMS [M+H]⁺: 502.10.

Example 218: Synthesis of(racemic)-1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one(I-325r)

(racemic)-1-(2-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared according to General Scheme 13 and General Scheme 5, step3, using(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneand acrylic acid. ¹H NMR 400 MHz (DMSO-d₆, 5:4 amide rotamer ratio,asterisks denote minor rotamer peaks): δ 12.76 (br s, 1H); 8.88 (t,J=6.1 Hz, 1H); 8.75-8.80* (m, 1H); 8.31 (s, 1H); 8.24* (s, 1H); 7.64(dd, J=6.5, 2.9 Hz, 1H); 7.57 (dd, J=8.5, 3.7 Hz, 1H); 7.48 (t, J=7.8Hz, 2H); 7.26 (t, J=7.4 Hz, 1H); 7.20 (s, 1H); 7.19 (d, J=5.0 Hz, 2H);7.08 (dd, J=16.6, 10.3 Hz, 1H); 7.03 (dd, J=8.3, 2.3 Hz, 1H); 6.60* (dd,J=16.8, 10.3 Hz, 1H); 6.14 (ddd, J=16.7, 3.8, 2.5 Hz, 1H); 5.65 (td,J=9.9, 2.5 Hz, 1H); 4.31-4.36 (m, 1H); 4.24-4.29* (m, 1H); 3.95-4.01 (m,1H); 3.68-3.82 (m, 1H); 3.55-3.67 (m, 1H); 3.39-3.49 (m, 2H); 3.39-3.49*(m, 1H); 1.86-2.03 (m, 3H); 1.81-1.89 (m, 1H). LCMS [M+H]⁺: 502.10.

General Procedure P One General Procedure for Vinysulfonamide Formation.

A solution of 2-chloroethanesulfonyl chloride (1.0 equiv) and Et₃N (1.0equiv) in DCM (18 mL/mmol) cooled to 0° C. was added dropwise to asuspension of secondary amine (38-A/B) (1.0 equiv) and Et₃N (1.0 equiv)in DCM (18 mL/mmol), also cooled to 0° C. After 15 minutes, the reactionmixture was washed with saturated aqueous NaHCO₃ (twice), dried overMgSO₄ and concentrated under vacuum. The residue was purified by normalphase chromatography (75%-100% EtOAc/hexanes).

Example 219: Synthesis of(racemic)-(2-chloro-4-phenoxyphenyl)(4-((1-(vinylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-322r)

(racemic)-(2-Chloro-4-phenoxyphenyl)(4-((1-(vinylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Scheme 13 and General Procedure P,using(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.¹H NMR 400 MHz (DMSO-d₆): δ 12.75 (br s, 1H); 8.84 (d, J=7.4 Hz, 1H);8.26 (s, 1H); 7.63 (s, 1H); 7.57 (d, J=8.5 Hz, 1H); 7.46 (s, 2H); 7.24(t, J=7.4 Hz, 1H); 7.18 (s, 1H); 7.17 (d, J=6.1 Hz, 2H); 7.01 (dd,J=8.5, 2.4 Hz, 1H); 6.79 (dd, J=16.5, 10.0 Hz, 1H); 6.10 (d, J=4.5 Hz,1H); 6.07 (d, J=11.0 Hz, 1H); 4.24-4.33 (m, 1H); 3.55 (d, J=11.2 Hz,2H); 3.18-3.23 (m, 1H); 2.88-2.99 (m, 2H); 1.83-1.97 (m, 2H); 1.56-1.72(m, 2H). LCMS [M+H]⁺: 538.10.

Example 220: Synthesis of(racemic)-(2-chloro-4-phenoxyphenyl)(4-(((1-(vinylsulfonyl)pyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-326r)

(racemic)-(2-Chloro-4-phenoxyphenyl)(4-(((1-(vinylsulfonyl)pyrrolidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Scheme 13 and General Procedure P,using(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.¹H NMR 400 MHz (DMSO-d₆): δ 12.75 (s, 1H); 8.85 (dd, J=6.7, 4.7 Hz, 1H);8.25 (s, 1H); 7.63 (d, J=2.7 Hz, 1H); 7.58 (d, J=8.5 Hz, 1H); 7.48 (dd,J=8.4, 7.3 Hz, 2H); 7.25 (t, J=7.4 Hz, 1H); 7.20 (s, 1H); 7.18 (d, J=6.1Hz, 2H); 7.03 (dd, J=8.4, 2.3 Hz, 1H); 6.93 (dd, J=16.5, 10.0 Hz, 1H);6.52 (s, 1H); 6.15 (d, J=10.2 Hz, 1H); 6.12 (d, J=3.7 Hz, 1H); 3.95-4.01(m, 1H); 3.86-3.90 (m, 1H); 3.54-3.60 (m, 1H); 3.19-3.27 (m, 2H);1.88-1.96 (m, 2H); 1.81-1.85 (m, 1H); 1.73-1.77 (m, 1H). LCMS [M+H]⁺:538.10.

Example 221: Synthesis of(racemic)-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)-1-(methylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-653) Step 1: Synthesis ofrac-methyl-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-16-sulfaneylidene)-5-oxohexanoate(653b)

To a solution of trimethylsulfonium iodide (4.5 g, 21 mmol) in dry DMSO(20 mL) is added tBuOK (2.1 g, 18 mmol) and the mixture is stirred for 1h at RT. rac-1-(tert-butyl) 2-methyl 5-oxopyrrolidine-1,2-dicarboxylate(653a) (5 g, 21 mmol) is then added and the mixture is stirred at roomtemperature for 3h. The mixture is then quenched by addition of waterand extracted with EtOAc. Combined organic phases are dried over MgSO₄,filtered and concentrated. Purification by chromatography (DCM/MeOH 9/1)yielded the title compound.

¹H NMR (CDCl₃): δ 5.44 (d, J=7.4 Hz, 1H), 4.38 (s, 1H), 4.29-4.24 (m,1H), 3.73 (s, 3H), 3.39-3.38 (m, 6H), 2.33-2.19 (m, 2H), 2.14-2.04 (m,1H), 1.98-1.89 (m, 1H), 1.42 (s, 9H).

Step 2: Synthesis of rac-1-(tert-butyl) 2-methyl5-oxopiperidine-1,2-dicarboxylate (653c)

A solution of methylrac-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-16-sulfaneylidene)-5-oxohexanoate(2.7 g, 8.0 mmol) and [Ir(COD)C_(1]2) (54 mg, 0.1 mmol) in DCE (80 mL)is degassed by bubbling argon for 20 min. The mixture is then heated atreflux for 2h. The mixture is then concentrated and then purified bynormal phase chromatography (gradient from 100% hexane to 100% EtOAc).¹H NMR (CDCl₃, 400 mHz): δ 4.82 (t, J=6.7 Hz, 0.5H), 4.58 (t, J=7.0 Hz,0.5H), 4.43-4.27 (m, 1H), 3.95-3.85 (m, 1H), 3.77 (s, 1H), 2.51-2.28 (m,3H), 2.21-2.04 (m, 1H), 1.46-1.43 (m, 9H).

Step 3: Synthesis of rac-1-(tert-butyl) 2-methyl5-hydroxypiperidine-1,2-dicarboxylate (653 d)

To a solution of rac-1-(tert-butyl) 2-methyl5-oxopiperidine-1,2-dicarboxylate (5.9 g, 22.9 mmol) in THF (200 mL) at−45° C. is added a solution of L-Selectride (1.0M, 27.5 mL, 37.5 mmol).The mixture is stirred for 1 h at −45° C. then quenched with saturatedaqueous NH₄Cl. The aqueous phase is extracted with EtOAc. Combinedorganic phases are dried over MgSO₄, filtered and concentrated. Thecrude is purified by chromatography (gradient from 100% hexane to 100%EtOAc). LCMS [M+Na]⁺: 282.1.

Step 4: Synthesis of rac-1-(tert-butyl) 2-methyl 5-((methylsulfonyl)oxy)piperidine-1,2-dicarboxylate (653e)

A solution of rac-1-(tert-butyl) 2-methyl5-hydroxypiperidine-1,2-dicarboxylate (2.4 g, 9.3 mmol), methanesulfonylchloride (788 μL, 10.2 mmol) and triethylamine (1.9 mL, 13.9 mmol) inDCM (50 mL) is stirred for 3h at room temperature. The mixture is thenwashed twice with a sat. aq. sol. of NaHCO₃, twice with HCl 1M and oncewith water, dried over MgSO₄, filtered and concentrated. The crude isused as is in the next step.

Step 5: Synthesis of rac-1-(tert-butyl) 2-methyl5-azidopiperidine-1,2-dicarboxylate (653f)

A solution of rac-1-(tert-butyl) 2-methyl 5-((methylsulfonyl)oxy)piperidine-1,2-dicarboxylate (2.70 g, 8.0 mmol) and sodiumazide (3.12 g, 48.0 mmol) in DMF (20 mL) is stirred overnight at 80° C.After cooling to room temperature the mixture is diluted in water andextracted with EtOAc. Combined organic phases are washed with 1M HCl,brine, dried over MgSO₄, filtered and concentrated. LCMS [M+Na]⁺: 307.1.

Step 6: Synthesis of rac-tert-butyl5-azido-2-(hydroxymethyl)piperidine-1-carboxylate (653g)

To a solution of rac-1-(tert-butyl) 2-methyl5-azidopiperidine-1,2-dicarboxylate (2.1 g, 7.4 mmol) in THF (70 mL) isadded ethanol (1.3 mL, 22.2 mmol) and lithium borohydride (2M, 11.1 mL,22.2 mmol) and the mixture is stirred overnight at room temperature. Themixture is then quenched with sat. aq. NaHCO₃ and extracted with EtOAc.Combined organic phases are dried over MgSO₄, filtered and concentrated.The crude is purified by chromatography (gradient from DCM to DCM/MeOH9/1). LCMS [M+Na]⁺: 279.0.

Step 7: Synthesis of rac-tert-butyl-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl) piperidine-1-carboxylate (653h)

A mixture ofrac-tert-butyl-5-azido-2-(hydroxymethyl)piperidine-1-carboxylate (700mg, 2.73 mmol), TBDPSCl (781 μL, 3.00 mmol) and imidazole (242 mg, 3.55mmol) in DMF (10 mL) is stirred overnight at room temperature. Themixture is then diluted in water and extracted with EtOAc. Combinedorganic phases are washed with brine, dried over MgSO₄, filtered andconcentrated. The crude is purified by chromatography (gradient fromhexane to hexane/EtOAc 1/1). LCMS [M+H-Boc]⁺: 395.2.

Step 8: Synthesis ofrac-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-ium2,2,2-trifluoroacetate (653i)

To a solution ofrac-tert-butyl-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-1-carboxylate(1.07 g, 2.17 mmol) in DCM (18 mL) is added TFA (2 mL) and the mixtureis stirred for 1 h at RT. The mixture is then concentrated to dryness,co-evaporated with DCM and the crude is brought on to the next stepwithout further purification. LCMS [M+H]: 395.2

Step 9: Synthesis ofrac-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)piperidine (653j)

To a solution of rac-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine (150 mg, 0.38 mmol) and triethylamine (264.9μL, 1.90 mmol) in DCM (3.75 mL) at 0° C. is added methanesulfonylchloride (32.4 μL, 0.42 mmol). The mixture is stirred for 2h at 0° C.then concentrated and the crude is purified by chromatography (gradientfrom 100% hexanes to 50% EtOAc/hexanes). LCMS [M+Na]: 495.1.

Step 10: Synthesis ofrac-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)piperidin-3-amine (653k)

To a solution of azide (653j) in methanol (0.1 M) is added Pd(OH)₂/C(10% w/w) and the mixture is stirred under hydrogen atmosphere at roomtemperature and atmospheric pressure. The mixture is then filteredthrough Celite and concentrated. The crude is used as is without furtherpurification. LCMS [M+H]: 447.2.

Step 11: Synthesis ofrac-(4-((6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(6531)

rac-(4-((6-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanonewas prepared according to General Procedure A, usingrac-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)piperidin-3-amine with 36-A. LCMS [M+H]: 794.3.

Step 12: Synthesis ofrac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)-1-(methylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-653)

rac-(4-((6-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanonein methanolic HCl solution (1.25M) was stirred at room temperature for 2hours then concentrated to dryness and purified by RP chromatography(gradient from 30% to 90% MeCN+0.1% formic acid in water. Two distinctisomers were observed but kept together. ¹H NMR (DMSO-d₆, 400 MHz):mixture of cis and trans isomers: δ 9.14 (d, J=7.2 Hz, 0.5H), 8.69 (d,J=7.2 Hz, 0.5H), 8.27 (s, 1H), 7.64 (s, 1H), 7.59-7.53 (m, 1H),7.50-7.46 (m, 1H), 7.28-7.23 (m, 1H), 7.19-7.17 (m, 1H), 7.04-7.01 (m,1H), 4.95 (bs, 1H), 4.34-4.32 (m, 0.5H), 4.12-3.99 (m, 1.5H), 3.90-3.84(m, 1.5H), 3.69-3.58 (m, 2H), 3.28-3.25 (m, 1H), 3.04 (s, 1.5H),3.59-2.84 (m, 2H), 2.07-1.61 (m, 4H). LCMS [M+H]: 556.1.

Example 222: Synthesis ofrac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-343r) Step 1: Synthesis ofrac-tert-butyl-5-amino-2-(hydroxymethyl)piperidine-1-carboxylate (343ra)

Analogous to the preparation of 653k, a solution of azide (653g) inmethanol (0.1 M) is added Pd(OH)₂/C (10% w/w) and the mixture is stirredunder hydrogen atmosphere at room temperature and atmospheric pressure.The mixture is then filtered through Celite and concentrated. The crudeis used as is without further purification. LCMS [M+H]: 231.2.

Step 2: Synthesis ofrac-tert-butyl-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)-piperidine-1-carboxylate(343rb)

rac-Tert-butyl-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)-piperidine-1-carboxylatewas prepared according General Procedure A, usingrac-tert-butyl-5-amino-2-(hydroxymethyl)piperidine-1-carboxylate with36-A. LCMS [M+H]: 578.3.

Step 3: Synthesis ofrac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-343r)

A solution of tert-butylrac-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)piperidine-1-carboxylate(113 mg, 0.19 mmol) in DCM (3 mL) is treated with trifluoroacetic acid(3 mL) for 1 h. The mixture is then concentrated to dryness and purifiedby preparative HPLC (gradient from 20% to 95% of acetonitrile+0.1%formic acid). ¹H NMR (DMSO-d₆, 400 mHz): δ 8.94 (d, J=6.3 Hz, 0.5H),8.65 (d, J=7.0 Hz, 0.5H), 8.21 (d, J=5.9 Hz, 1H), 7.61 (d, J=7.4 Hz,1H), 7.51-7.42 (m, 3H), 7.21-7.19 (m, 1H), 7.15-7.11 (m, 3H), 6.98-6.95(m, 1H), 5.26 (bs, 0.5H), 5.06 (bs, 0.5H), 4.25-4.30 (m, 1H), 3.54-3.33(m, 3H), 3.03-2.96 (m, 1.5H), 2.80-2.60 (m, 0.5H), 2.11-2.10 (m, 0.5H),1.86-1.81 (m, 1.5H), 1.67-1.62 (m, 1.5H), 1.45-1.42 (m, 0.5H). LCMS[M+H]: 478.2.

Example 223: Synthesis ofrac-1-(5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)-piperidin-1-yl)ethan-1-one(I-654)

A mixture ofrac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-343r) (30 mg, 0.063 mmol), sodium acetate (5.7 mg, 0.069 mmol), EDCI(12.6 mg, 0.066 mmol), HOAt (9.0 mg, 0.066 mmol) and DIPEA (32.8 μL,0.19 mmol) in DCM (0.5 mL) is stirred at RT for 24h. The mixture is thenconcentrated to dryness and purified by RP (gradient from 35% to 90%MeCN+0.1% formic acid). ¹H NMR (DMSO-d₆, 400 mHz): (mixture ofcis/trans, presence of rotamers) δ 9.09-9.04 (m, 1H), 8.74-8.69 (m, 1H),8.44 (s, 1H), 8.26-8.23 (m, 1H), 7.61-7.54 (m, 3H), 7.50-7.46 (m, 3H),7.27-7.24 (m, 1H), 7.20-7.18 (m, 3H), 7.03-7.01 (m, 1H), 4.98-4.66 (m,2H), 4.63-4.31 (m, 2H), 4.20-3.89 (m, 3H), 3.75-3.70 (m, 1H), 3.64-3.13(m, 18H+H₂O), 2.94-2.84 (m, 1H), 2.45-2.39 (m, 1H), 2.12-1.52 (m, 10H).LCMS [M+H]: 520.2.

Example 224: Synthesis of(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-345e) Step 1: Synthesis of tert-butyl(2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(345ea)

Tert-butyl(2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylatewas prepared according to Procedure A using tert-butyl(2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate and 36-A.LCMS [M+H]⁺: 564.3, 566.3.

Step 2: Synthesis of(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-345e)

(2-Chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Scheme 15. To a solution of tert-butyl(2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)-pyrrolidine-1-carboxylate(42 mg, 0.0746 mmol) in DCM (2 mL) was added TFA (1 mL) and the solutionstirred 2 h at room temperature. The reaction mixture was concentratedunder reduced pressure and the residue co-distilled with MeCN. Theresidue was dissolved in water and lyophilized affording(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneas the trifluoroacetate salt (50.5 mg, 0.073 mmol, 98%). ¹H NMR(DMSO-d₆, 400 mHz): δ 12.89 (s; 1H); 9.38 (s; 1H); 8.92 (d; J=5.85 Hz;1H); 8.70 (s; 1H); 8.32 (s; 0.7H); 7.72 (s; 1H); 7.55 (d; J=8.47 Hz;1H); 7.49 (m; 2H); 7.26 (t; J=7.40 Hz; 1H); 7.18-7.22 (m; 3H); 7.03 (dd;J=8.46; 2.37 Hz; 1H); 4.75-4.79 (m; 1H); 3.90 (t; J=7.26 Hz; 1H); 3.74(dd; J=11.75; 3.80 Hz; 1H); 3.66 (dd; J=11.53; 5.78 Hz; 1H); 3.60 (dd;J=11.88; 7.00 Hz; 1H); 3.24-3.31 (m; 1H); 2.22 (d; J=7.77 Hz; 1H); 2.16(s; 1H). LCMS [M+H]⁺: 464.20, 466.2.

Example 225: Synthesis of(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-342e)

(2-Chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonetrifluoroacetate (68.8 mg, 0.1045 mmol) was suspended in concentratedammonium hydroxide solution, water was added and the mixturelyophilized. The solid residue was dissolved in 2,2,2-trifluoroethanol(2.6 mL). Paraformaldehyde (25.1 mg, 0.8311 mmol) and sodium borohydride(5.5 mg, 0.1463 mmol) were added and the mixture stirred at roomtemperature overnight. MeOH (1 mL) was added and the mixture stirred 30min at RT. The solution was concentrated under reduced pressure. Theresidue was dissolved in water (1 mL) and DMSO (0.5 mL), filteredthrough a Teflon filter and purified by preparative HPLC, 10% MeCN (5min), 5% to 80% MeCN (30 min) in water, the tubes containing the productwere lyophilized affording(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(18 mg, 0.0344 mmol, 33%). ¹H NMR (DMSO-d₆, 400 mHz): δ 8.84 (d; J=6.81Hz; 1H); 8.25 (s; 2H); 7.62 (s; 1H); 7.58 (d; J=8.45 Hz; 1H); 7.46-7.50(m; 2H); 7.26 (t; J=7.34 Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd; J=8.46;2.36 Hz; 1H); 4.50-4.54 (m; 1H); 3.45-3.49 (m; 2H); 3.33 (m; 2H); 2.34(s; 3H); 2.21 (t; J=8.54 Hz; 1H); 2.13 (dt; J=13.03; 8.02 Hz; 1H);1.76-1.83 (m; 1H). LCMS [M+H]⁺: 478.25, 480.20.

Example 226: Synthesis of1-((2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one(I-655)

1-((2S,4R)-4-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-onewas prepared according to General Scheme 15. A solution of(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(30 mg, 0.0434 mmol) was dissolved in 0.3 mL 1N HCl and 5 mL water andlyophilized. The product was dissolved in DMF (0.4 mL). DIPEA (16.61 ml,0.0954 mmol) was added and the solution was stirred 30 min at roomtemperature. AcONa (3.7 mg, 0.0455 mmol), HOAt (5.9 mg, 0.0434 mmol) andEDCI (8.3 mg, 0.0434 mmol) were added at room temperature and thereaction mixture stirred overnight. The crude was diluted with DMF,water was added and the solution concentrated under reduced pressure.The residue was dissolved in water (1 mL) and DMSO (0.5 mL), filteredthrough a Teflon filter and purified by preparative HPLC, 10% MeCN (5min), 5% to 80% MeCN (30 min) in water.1-((2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one (23.5 mg, 0.0452 mmol, 46%) was isolated asa white solid after lyophilization. ¹H NMR (DMSO-d₆, 400 mHz): δ 8.88(t; J=6.02 Hz; 1H); 8.44 (s; 0.3H); 8.27 (d; J=3.14 Hz; 1H); 7.62 (d;J=3.06 Hz; 1H); 7.57 (dd; J=8.46; 1.82 Hz; 1H); 7.46-7.50 (m; 2H); 7.25(t; J=7.40 Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd; J=8.45; 2.37 Hz; 1H);4.78-4.87 (m; 1.7H); 4.10 (d; J=6.86 Hz; 1H); 3.94 (dd; J=10.29; 6.78Hz; 0.7H); 3.64 (t; J=6.50 Hz; 0.3H); 2.33-2.37 (m; 3.3H); 2.03 (s; 1H);1.97-2.00 (m; 1H); 1.95 (s; 2H). LCMS [M+H]⁺: 506.2, 508.2.

Example 227: Synthesis of(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-656) Step 1: Synthesis of tert-butyl(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (656a)

To a solution of tert-butyl(2S,4R)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate (see J. Org.Chem. 2003, 68, 4439-4445 for preparation procedures) (400 mg, 1.65mmol) in DMF (8.2 mL), TBDPSCl (472 mL, 1.82 mmol) and imidazole (123.6mg, 1.82 mmol) were added and the reaction mixture was stirred overnightat room temperature. The crude mixture was diluted with EtOAc, washedwith water and brine, dried over anhydrous sodium sulfate andconcentrated tio drieness. The crude mixture was purified by flashchromatography, ISCO, 12 g column, (EtOAc/hexanes mixture) 0% EtOAc (3min), 0% to 5% EtOAc (12 min, 5% EtOAc (3 min) affording tert-butyl(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-1-carboxylate(570 mg, 1.1858 mmol, 72%) as a transparent oil. ¹H NMR (CDCl₃, 400mHz): δ 7.72 (dd; J=7.39; 1.88 Hz; 1H); 7.62-7.64 (m; 2H); 7.36-7.43 (m;5H); 3.96-4.17 (m; 2H); 3.49-3.75 (m; 2H); 2.24 (t; J=46.59 Hz; 1H);1.59 (s; 1H); 1.48 (s; 2H); 1.07 (s; 4H); 1.05 (s; 5H). LCMS

Step 2: Synthesis of(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine(656b)

To a solution of tert-butyl(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-1-carboxylate(42 mg, 0.0746 mmol) in DCM (2 mL) was added TFA (1 mL) and the solutionstirred 2 h at room temperature. The reaction mixture was concentratedunder reduced pressure and the residue codestilled with MeCN. Theresidue was suspended in EtOAc, washed with saturated sodiumbicarbonate, dried over anhydrous sodium sulfate and concentrated underreduced pressure affording(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine asthe TFA salt (50.5 mg, 0.073 mmol, 98%). LCMS 381.3 [M+H]⁺.

Step 3: Synthesis of(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidine(656c)

(2S,4R)-4-Azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine (70mg, 0.18 mmol) was dissolved in 0.5 mL of dry dichloromethane, cooled to0° C., DIPEA (128 mL, 0.74 mmol) was added followed by methanesulfonylchloride (15.7 mL, 22.42 mmol). The reaction mixture was stirred at roomtemperature under N₂ for about 8 hours and diluted with dichloromethane.The reaction mixture was washed with 1N HCl, saturated aqueous Na₂CO₃and water. The organic phase was dried over anhydrous sodium sulfate andconcentrated under reduced pressure affording(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidine (42.3 mg, 0.0922 mmol, 50%) as a white solid. ¹H NMR (CDCl₃,400 mHz): δ 7.66 (m; 4H); 7.37-7.46 (m; 6H); 4.21 (t; J=4.01 Hz; 1H);3.81-3.87 (m; 3H); 3.46-3.55 (m; 2H); 2.84 (s; 3H); 2.30-2.36 (m; 1H);2.21 (m; 1H); 1.08 (s; 9H). LCMS 481.2 [M+Na]⁺.

Step 4: Synthesis of(3R,5S)-5-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidin-3-amine (656d)

A mixture of(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidine (42.3 mg, 0.09 mmol) and 10% palladium on carbon (5 mg) inmethanol (10 mL) was stirred under 1 atm of hydrogen at room temperaturefor 16 h. The catalyst was filtered off through a Teflon filter and thefiltrate afforded(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidin-3-amine(39 mg, 0.0901 mmol, 98%) as an oil after evaporation. LCMS 433.2[M+H]⁺.

Step 5: Synthesis of(4-(((3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(656e)

(4-(((3R,5S)-5-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidine-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone was prepared according General Procedure A with(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidin-3-amine (656d)and 36-A. LCMS 780.3, 782.3 [M+H]⁺.

Step 6: Synthesis of(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-656)

(2-Chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Scheme 16. A solution of(4-(((3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylpyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(83.4 mg, 0.116 mmol) in 1.25N HCl in MeOH was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure and the residue purified by preparative HPLC (5% to 80% MeCN inwater, 0.1% TFA, 30 min) affording(4-(((3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(11.9 mg, 0.022 mmol, 32%) as a white solid after lyophilization. ¹H NMR(DMSO-d₆, 400 mHz): δ 8.87 (d; J=6.13 Hz; 1H); 8.37 (s; 0.2H); 8.30 (s;1H); 7.67 (s; 1H); 7.56 (d; J=8.46 Hz; 1H); 7.48 (m; 2H); 7.25 (t;J=7.40 Hz; 1H); 7.19 (m; 3H); 7.03 (dd; J=8.45; 2.37 Hz; 1H); 4.96 (brs; 1H); 4.70 (d; J=6.59 Hz; 1H); 3.86 (s; 1H); 3.72 (dd; J 10.15; 5.62Hz; 1H); 3.61 (d; J=8.71 Hz; 1H); 3.46 (t; J=8.81 Hz; 1H); 3.30-3.32 (m;1H); 2.89 (s; 3H); 2.36-2.42 (m; 1H); 2.11-2.18 (m; 1H). LCMS[M+H]⁺:542.2, 544.2.

Example 228: Synthesis of(2-chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-369e) Step 1: Synthesis of 1-(tert-butyl) 2-methyl (2S,4S)-4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (369ea)

To a solution of 1-(tert-butyl) 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.766 mmol) inDCM (100 mL) at 0° C. was added MsCl (3.8 mL, 49.096 mmol) followed byslow addition of DIPEA (8.5 mL, 48.801 mmol). After the addition, thereaction mixture was allowed to warm up to rt and stirred for 5 hours.The reaction mixture was poured into a cooled aqueous saturated NH₄Cl(250 mL). The layers were partitioned and the aqueous layer wasextracted with DCM (80 mL). The combined organic layers were washed withaqueous saturated NaHCO₃(250 mL), water (250 mL) and brine. It was driedover MgSO₄, filtered and concentrated to dryness to afford 13 g of thedesired product as a yellow oil which was used as such in the subsequentstep without further purification.

Step 2: Synthesis of tert-butyl(2S,4S)-2-(hydroxymethyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (369eb)

To a solution of 1-(tert-butyl) 2-methyl(2S,4S)-4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (500 mg,1.546 mmol) in THE (125 mL) at 0° C. was added LiBH₄ (2 M, 39 mL, 78.0mmol) followed by slow addition of methanol (3.13 mL, 77.27 mmol). Thereaction mixture was allowed to warm up slowly to rt and stirred at rtfor 18 h. Acetone (10 mL) was added slowly, stirred for 1 h, then themixture was poured into a cooled aqueous saturated NH₄Cl (300 mL). Themixture was extracted with EtOAc (2×80 mL). The combined organic layerswere washed with water (100 mL) and brine, dried over MgSO₄, filteredand concentrated to dryness to afford 11.37 g of the desired product asa colorless solid which was used as such in the subsequent step withoutfurther purification. LCMS [M+Na]⁺: 318.1.

Step 3: Synthesis of tert-butyl(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)-pyrrolidine-1-carboxylate(369ec)

To a solution of tert-butyl(2S,4S)-2-(hydroxymethyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate(11.37 g, 35.16 mmol) in DCM (100 mL) at rt were added imidazole (4.8 g,70.505 mmol) and TBDPS-Cl (11.0 mL, 42.30 mmol). The reaction mixturewas stirred at rt for 18 hours. The mixture was diluted with water (100mL) and DCM (50 mL). The layers were partitioned and DCM layer waswashed with brine, dried over MgSO₄, filtered and concentrated todryness to afford 18.5 g of the desired product as a colorless gum whichwas used as such in the subsequent step without further purification.LCMS [M+Na]⁺: 556.3.

Step 4: Synthesis of tert-butyl(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)-pyrrolidine-1-carboxylate(369ed)

To a solution of tert-butyl(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate(18 g, 33.723 mmol) in DMF (100 mL) at rt was added sodium cyanide (2 g,40.808 mmol). The reaction mixture was heated to 80° C. for 18 hours.Upon cooling to rt, the reaction mixture was diluted with EtOAc (30 mL)and water (30 mL). The layers were partitioned and the aqueous layer wasextracted with EtOAc (15 mL). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated to dryness. Theresidue was purified by flash chromatography on silica gel eluting with10 and 15% EtOAc/hexanes to afford 6 g of the desired material as acolorless gum. LCMS [M+Na]⁺: 487.3.

Step 5: Synthesis of tert-butyl(2S,4S)-4-(aminomethyl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (369ee)

To a solution of tert-butyl(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate(220 mg, 0.473 mmol) in ethanol (3 mL) at 0° C. was added nickelchloride (II) (62 mg, 0.478 mmol) followed by portion wise addition ofNaBH₄ (68 mg, 1.798 mmol). The reaction mixture was allowed to stir atrt for 6 hours. TLC showed complete reaction. The mixture was cooled to0° C. and 10% NH₄OH (20 mL) was added slowly, extracted with EtOAc (2×25mL). The combined organic layers were washed with water (2×20 mL) andbrine (20 mL), dried over MgSO₄, filtered and concentrated to dryness toafford 200 mg of the desired product as a light yellow oil. The crudematerial was used as such in the subsequent step without furtherpurification. LCMS [M+Na]⁺: 491.3.

Step 6: Synthesis of tert-butyl(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylate(369ef)

Prepared according to General Procedure A using tert-butyl(2S,4S)-4-(aminomethyl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-1-carboxylateand 36-A. LCMS [M+H]⁺: 816.3.

Step 7: Synthesis of(2-chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-369e)

(2-Chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Error! Reference source not found.using General Procedure. Product was isolated as a formate salt afterreverse phase purification (Biotage C18, 5-80% CH₃CN/H₂O+0.1% formicacid). ¹H NMR (DMSO-d₆, 400 mHz): δ 8.84 (t; J=5.66 Hz; 1H); 8.35 (s;1H); 8.24 (s; 1H); 7.63 (s; 1H); 7.58 (d; J=8.46 Hz; 1H); 7.48 (t;J=7.82 Hz; 2H); 7.25 (t; J=7.40 Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd;J=8.45; 2.37 Hz; 1H); 3.55-3.60 (m; 2H); 3.40-3.48 (m; 4H); 3.22 (dd;J=11.02; 7.02 Hz; 1H); 2.82 (dd; J=10.96; 7.04 Hz; 1H); 2.54-2.60 (m;1H); 1.73-1.78 (m; 2H). NH of indole not observed. LCMS [M+H]⁺: 478.1.

Example 229: Synthesis of(2-chloro-4-phenoxyphenyl)(4-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-370e)

To a solution of(2-chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(500 mg, 1.372 mmol) in 2,2,2-trifluoroethanol (5 mL) at rt were addedparaformaldehyde (330 mg, 10.989 mmol) and sodium borohydride (73 mg,1.930 mmol). The reaction mixture was stirred at rt for 18 hours. LCMSshowed complete reaction. The reaction mixture was diluted with (1:1)aqueous sat. NaHCO₃/water (30 mL) and EtOAc (30 mL). The layers werepartitioned and the aqueous layer was extracted with EtOAc (20 mL). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated to dryness. The residue was purified byreverse phase C18 ISCO CombiFlash (13 g column) eluting with 5-80%CH₃CN/water (0.1% formic acid) over 25 minutes. The product fractionswere combined and concentrated to dryness. The residue was freeze driedto afford 22 mg of the title compound as a colorless powder. ¹H NMR(DMSO-d₆, 400 mHz): δ 8.79 (t; J=5.41 Hz; 1H); 8.24 (s; 2H); 7.62 (s;1H); 7.58 (d; J=8.46 Hz; 1H); 7.48 (dd; J=8.45; 7.27 Hz; 2H); 7.25 (t;J=7.39 Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd; J=8.44; 2.37 Hz; 1H); 3.55(t; J=6.31 Hz; 2H); 3.43 (dd; J 10.90; 4.63 Hz; 1H); 3.30 (dd; J=10.90;5.90 Hz; 1H); 3.17 (t; J=7.86 Hz; 1H); 2.41-2.46 (m; 2H); 2.33 (s; 3H);2.13 (t; J=9.33 Hz; 1H); 1.77-1.82 (m; 1H); 1.67-1.72 (m; 1H). LCMS[M+H]⁺: 492.3.

Example 230: Synthesis of(4-((((3S,5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(I-657) Step 1: Synthesis of(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-carbonitrile(657a)

Tert-butyl(2S,4R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-cyanopyrrolidine-1-carboxylate(3 g, 4.639 mmol) in DCM (30 mL) at 0° C. was added TFA (10 mL, 130.591mmol). The reaction mixture was allowed to stir at rt for 3 hours.Toluene (15 mL) was added and the volatiles were removed under reducedpressure. The residue was dissolved in EtOAc (40 mL) and aqueous sat.NaHCO₃(50 mL) was added (pH˜8). The layers were partitioned and theaqueous layer was extracted with EtOAc (30 mL). The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated to dryness under reduced pressure to 1.7 g of the desiredproduct as a red oil. This crude material was used as such in thesubsequent step without further purification. LCMS [M+H]⁺: 365.3.

Step 2: Synthesis of(3R,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-carbonitrile(657b)

To a solution of(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-carbonitrile(500 mg, 1.372 mmol) in acetonitrile (5 mL) at rt were added potassiumcarbonate (569 mg, 4.117 mmol) and benzyl bromide (0.163 mL, 1.370mmol). The reaction mixture was stirred at rt for 18 hours. LCMS showedcomplete reaction. The reaction mixture was diluted with water (30 mL)and EtOAc (30 mL). The layers were partitioned and the aqueous layer wasextracted with EtOAc (20 mL). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated to dryness. Theresidue was purified by ISCO CombiFlash (24 g column) eluting with 0-50%EtOAc/hexanes to afford 480 mg of the desired product as a colorlessoil. LCMS [M+H]⁺: 455.1.

Step 3: Synthesis of(((3S,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-3-yl)methanamine(657c)

To a solution of(3R,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-carbonitrile(480 mg, 1.056 mmol) in ethanol (4 mL) at 0° C. was added nickelchloride (II) (137 mg, 1.057 mmol) followed by portion wise addition ofNaBH₄ (152 mg, 4.018 mmol). The reaction mixture was allowed to stir atrt for 6 hours. Additional nickel chloride (II) (137 mg, 1.057 mmol)followed by portionwise addition of NaBH₄ (152 mg, 4.018 mmol) and themixture was allowed to stir at rt for 18 hours. The mixture was cooledto 0° C. and 10% NH₄OH (20 mL) was added slowly, extracted with EtOAc(2×30 mL). The combined organic layers were washed with water (2×30 mL)and brine (30 mL), dried over MgSO₄, filtered and concentrated todryness to afford 430 mg of the desired product as a light yellow oil.The crude material was used as such in the subsequent step withoutfurther purification. LCMS [M+H]⁺: 459.3.

Step 4: Synthesis of(4-((((3S,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(657d)

According to General Procedure A, using(4-((((3S,5S)-1-benzyl-5-(((tert-butyl diphenylsilyl)oxy)methyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanoneand((3S,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-3-yl)methanamine.LCMS [M+H]⁺: 806.4.

Step 5: Synthesis of(4-((((3S,5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone(I-657)

(4-((((3S,5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanonewas prepared according to General Procedure H. The product was isolatedas formate salt after purification (Biotage C18, 5-85% acetonitrile inwater+0.1% formic acid). ¹H NMR (DMSO-d₆, 400 mHz): δ 12.71 (br s; 1H);8.74-8.77 (m; 1H); 8.22 (s; 1H); 7.60 (s; 1H); 7.56 (d; J=8.46 Hz; 1H);7.46-7.50 (m; 2H); 7.26-7.32 (m; 5H); 7.16-7.23 (m; 4H); 7.02 (dd;J=8.45; 2.37 Hz; 1H); 4.03-4.06 (m; 1H); 3.51-3.54 (m; 2H); 3.28-3.46(m; 3H); 2.99 (dd; J=8.87; 6.52 Hz; 1H); 2.74-2.79 (m; 1H); 2.33-2.46(m; 1H); 2.08-2.13 (m; 1H); 1.82-1.89 (m; 1H); 1.68-1.75 (m; 1H).Contained 0.48 eq. of formic acid at 8.14 ppm. LCMS [M+H]⁺: 568.3.

Example 231: Synthesis of(2-chloro-4-phenoxyphenyl)(4-((((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-362e)

(2-Chloro-4-phenoxyphenyl)(4-((((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Procedure A, using 36-A and((2S,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)methanol. ¹H NMR (DMSO-d₆,400 mHz): δ 8.82 (t; J=5.57 Hz; 1H); 8.43 (s; 0.16H); 8.22 (s; 1H); 7.6(s, 1H), 7.57 (m; 2H); 7.48 (d; J=8.45 Hz; 1H); 7.25 (t; J=7.40 Hz; 1H);7.18-7.20 (m; 3H); 7.03 (dd; J=8.44; 2.37 Hz; 1H); 4.61 (s; 1H); 4.10(t; J=5.74 Hz; 1H); 3.87 (t; J=5.91 Hz; 1H); 3.61-3.72 (m; 2H);3.37-3.47 (m; 2H); 1.86-1.95 (m; 2H); 1.63-1.69 (m; 2H). LCMS [M+H]⁺:479.2, 481.2.

Example 232: Synthesis ofracemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-359e) Step 1: Synthesis of methyl 6-((hydroxyimino)methyl)picolinate(359ea)

To methyl 5-formylpicolinate (1.0 g, 6.055 mmol) dissolved inethanol-water (14.4 mL, 2:1) was added hydroxylamine hydrochloride(0.463 g, 6.66 mmol) and sodium acetate (0.546 mg, 0.6661 mmol). Thereaction mixture was stirred overnight at 55° C. The reaction wasconcentrated under reduced pressure and redissolved in EtOAc (100 mL).The organic phase was washed with water, dried over sodium sulfate,filtered and concentrated under reduced pressure. The solid residue wasdissolved triturated with EtOAc, filtered and dried under reducedpressure affording methyl 6-(hydroxyimino)methyl)picolinate (990 mg,5.495 mmol, 91%) as a beige solid. LCMS [M+H]⁺: 181.1.

Step 2: Synthesis of racemic-cis-methyl6-(aminomethyl)piperidine-2-carboxylate dihydrochloride (359eb)

To a suspension of methyl 6-(hydroxyimino)methyl)picolinate (200 mg,1.161 mmol) and PtO₂ (26.37 mg, 0.116 mmol) in EtOH (5.8 mL), conc. HCl(0.2 mL) was added and the mixture was stirred over night under hydrogen(1 atm), the crude was filtered through Celite and concentrated underreduced pressure. The residue was dissolved in water and lyophilizedaffording a cis-isomer mixture of methyl6-(aminomethyl)piperidine-2-carboxylate dihydrochloride (343 mg, 1.366mmol, 100%) as a white solid. ¹H NMR (D₂O, 400 mHz): δ 4.03 (dd;J=12.04; 3.58 Hz; 1H); 3.71 (s; 23H); 3.49 (dtd; J=12.46; 6.29; 2.93 Hz;1H); 3.29 (dd; J=13.80; 5.98 Hz; 1H); 3.16 (dd; J=13.81; 6.76 Hz; 1H);2.24 (d; J=10.21 Hz; 1H); 1.91-1.99 (m; 2H); 1.52-1.64 (m; 2H); 1.43 (t;J=13.38 Hz; 1H). LCMS [M+H]⁺: 173.2.

Step 3: Synthesis of racemic-cis-1-benzyl 2-methyl6-((((benzyloxy)carbonyl) amino) methyl)piperidine-1,2-dicarboxylate(359ec)

A cis-isomer mixture of methyl 6-(aminomethyl)piperidine-2-carboxylatedihydrochloride (300 mg, 1.195 mmol), CbzCl (374 mL, 2.63 mmol),saturated sodium bicarbonate in water (6.5 mL) and dioxane (6.5 mL) wasstirred overnight at room temperature. The mixture was diluted withEtOAc, the phases separated. The aqueous phase extracted with EtOAc. Thecombined organic phases were combined and dried over anhydrous sodiumsulfate. The solution was concentrated under reduced pressure and theresidue purified bu flash chromatography (ISCO, 12 g column, EtOAc inhexanes) affording a cis-isomer mixture of 1-benzyl 2-methyl6-((((benzyloxy) carbonyl)amino)methyl)piperidine-1,2-dicarboxylate(OS03-034A1) (543.1 mg, 1.23 mmol, 62%) as a transparent syrup. LCMS[M+H]⁺: 441.3.

Step 4: Synthesis of racemic-cis-benzyl2-((((benzyloxy)carbonyl)amino)methyl)-6-(hydroxymethyl)piperidine-1-carboxylate(359ed)

A solution of 2M lithium borohydride in THF (0.62 mL, 1.23 mmol) wasadded to a solution of a mixture of cis-isomers of 1-benzyl 2-methyl6-((((benzyloxy)carbonyl)amino)methyl) piperidine-1,2-dicarboxylate(543.1 mg, 1.23 mmol) in diethylether (3.5 mL) at 0° C. The reactionmixture was stirred at 0° C. 2 h. A saturated aqueous sodium bicarbonatesolution was added dropwise, the mixture was stirred 1 h at roomtemperature. The layers were separated. The aqueous layer extracted withdiethyl ether, the organic phased were combined, dried over anhydroussodium sulfate and concentrated under reduced pressure affording acis-isomer mixture of benzyl2-((((benzyloxy)carbonyl)amino)methyl)-6-(hydroxymethyl)piperidine-1-carboxylate(270 mg, 0.654 mmol, 100%) as transparent syrup. LCMS [M+H]⁺: 413.2.

Step 5: Synthesis of racemic-cis-6-(aminomethyl)piperidin-2-yl)methanol(359ee)

To a suspension of a cis-isomer mixture of benzyl2-((((benzyloxy)carbonyl)amino)methyl)-6-(hydroxymethyl)piperidine-1-carboxylate(270 mg, 0.654 mmol) and 20% palladium hydroxide on carbon (130 mg) inMeOH (15 mL), 1N HCl (2 mL) was added and the mixture was stirredovernight under hydrogen (1 atm), the crude was filtered through Celiteand concentrated under reduced pressure. The residue was dissolved inwater and lyophilized affording a cis-isomer mixture of6-(aminomethyl)piperidin-2-yl)methanol dihydrochloride (140 mg, 0.65mmol, 100%) as a white solid. LCMS [M+H]⁺: 145.1.

Step 6: Synthesis ofracemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-359e)

Racemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanonewas prepared according to General Procedure A, using a cis-isomermixture of 6-(aminomethyl)piperidin-2-yl)methanol dihydrochloride and36-A. ¹H NMR (DMSO-d₆, 400 mHz): δ 8.86 (t; J=5.71 Hz; 1H); 8.32 (s;0.1H); 8.25 (s; 2H); 7.63 (s; 1H); 7.57 (d; J=8.46 Hz; 1H); 7.46-7.50(m; 2H); 7.26 (t; J=7.40 Hz; 1H); 7.18-7.20 (m; 3H); 7.03 (dd; J=8.45;2.37 Hz; 1H); 3.60-3.66 (m; 1H); 3.51-3.57 (m; 1H); 3.40 (dd; J=10.64;4.31 Hz; 1H); 3.26 (dd; J=10.64; 7.23 Hz; 1H); 2.93 (br s; 1H); 2.68 (brs; 1H); 1.77 (m; 2H); 1.55 (d; J=12.64 Hz; 1H); 1.36 (q; J=12.90 Hz;1H); 1.18 (q; J=12.16 Hz; 1H); 1.03 (q; J=12.11 Hz; 1H). LCMS [M+H]⁺:492.2, 494.2.

Example 233: Synthesis ofracemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)-1-methylpiperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-360e)

A cis-isomer mixture of(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I-359e) (20.9 mg, 0.0421 mmol) was dissolved in 2,2,2-trifluoroethanol(1.05 mL), paraformaldehyde (10.1 mg, 0.3367 mmol) and sodiumborohydride (2.2 mg, 0.0589 mmol) were added and the mixture stirred atRT overnight. MeOH (1 mL) was added and the mixture stirred 30 min atroom temperature. The solution was concentrated under reduced pressure.The residue was purified by preparative HPLC 10% to 85%0 MeCN in water).The fractions containing the product were combined and lyophilizedaffording a mixture of(2-chloro-4-phenoxyphenyl)(4-((((2R,6S)-6-(hydroxymethyl)-1-methylpiperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneand(2-chloro-4-phenoxyphenyl)(4-((((2S,6R)-6-(hydroxymethyl)-1-methylpiperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(10.1 mg, 0.0183 mmol, 43%) as a white powder. ¹H NMR (DMSO-d₆, 400mHz): δ 8.90 (t; J=4.88 Hz; 1H); 8.24 (s; 1H); 8.22 (s; 1H); 7.56-7.59(m; 2H); 7.48 (m; 2H); 7.25 (t; J=7.39 Hz; 1H); 7.18-7.20 (m; 3H); 7.02(dd; J=8.45; 2.37 Hz; 1H); 3.60-3.67 (m; 2H); 3.40-3.49 (m; 2H); 2.43(s; 1H); 2.30 (s; 3H); 2.23 (s; 1H); 1.72 (s; 1H); 1.60-1.64 (m; 2H);1.47 (d; J=13.15 Hz; 1H); 1.32 (s; 2H). LCMS [M+H]⁺: 506.26,

Example 234: BTK Kinase Activity Assay

Radiometric Assay

Enzyme assay using full length recombinant active form of wild-type BTKand BTK-C481 S was measured as described previously (Anastassiadis T, etal., Nat. Biotechnol. 29(11):1039-45 (2011)). Compounds were tested in10-point dose IC₅₀ mode with 3-fold serial dilution starting at 1 or 10μM concentration. BTK kinase activity was assayed in a buffer solutioncontaining 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35,0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. Compounds in 100% DMSOwere mixed with kinase (8 nM wild-type BTK or 5 nM BTK-C481S mutant)with substrate into the kinase reaction mixture by Acoustic technology(Echo550; nanoliter range) and incubated for 20 min at room temp. Thereaction was initiated by adding 10 μM ATP containing ³³P-ATP into themixture and incubated for 2 hours at room temperature. Kinase activitywas detected by P81 filter-binding ³³P radioisotope based radiometricmethod. All compounds were tested in duplicate. The raw data was fit toa 4-parameter logistic model to derive the IC₅₀ value for kinaseactivity inhibition.

Mobility Shift Assay (MSA)

Compounds were tested either in the inactive or active BTK assays onCaliper LabChip microfluidic mobility shift assay platform.

Full length unphosphorylated form of BTK expressed in Sf9 cells wasemployed to test inhibitory activity in the inactive BTK assay. Theassay was measured in buffer solution containing 100 mM HEPES pH7.5,0.01% Triton X-100, 0.1% BSA, 5 mM MgCl2.1 mM DTT. The enzyme andincreasing concentrations of inhibitor was incubated at room temperaturefor 30 minutes and the kinase reaction was initiated by the addition anactivation mixture diluted in assay buffer containing Srctide peptidesubstrate, DOPS/DOPC, PtdIns(3,4,5)P3, and ATP for final concentrationsof 1 μM Srctide, 5.5 μM DOPS, 5.5 μM DOPC, 0.5 μM PtdIns(3,4,5)P3, and16 μM ATP. The plates were incubated for 60 minutes at room temperature,and then the reaction stopped with 100 mM HEPES buffer containing 0.01%Triton and 40 mM EDTA and read on Caliper Life Sciences Labchip EZReader II instrument.

The active BTK assay consisted of phosphorylated form of full lengthBTK. The assay was performed in a buffer solution utilized in theinactive BTK assay. The enzyme inhibitor complexes was incubated for 30minutes at the room temperature and the kinase activation reaction wasinitiated by the addition of 1 M Srctide peptide substrate and 16 M ATP.After incubation at room temperature for 60 minutes, the reaction wasstopped and the mobility shift was measured as described above for theinactive BTK assay. The data of inactive and active BTK assays was fitto a 4 parameter logistic model to calculate the IC₅₀ value.

Alpha Screen Assay

Purified full-length inactive BTK (wild type and C₄₈₁ mutant, N-terminal6×HIS tagged BTK, Mwt=78.2 kDa) were activated using soluble inositolhexakisphosphate (IP6) and ATP as described (Q. Wang, E. M. Vogan, L. M.Nocka, C. E. Rosen, J. A. Zorn, S. C. Harrison J. Kuriyan, eLife 2015;4:e06074), with minor modification. To 190 μl of 1 mM IP6 in activationbuffer (25 mM Tris, pH 7.5, 150 mM NaCl, 5% glycerol) was added 10 μl ofinactive BTK at 5-6 mg/ml and incubated for 10 min at room temperaturefollowed by addition of 200 μl of 2 mM ATP in assay buffer (50 mM Tris,pH 8, 10 mM MgCl2, 1 mM EDTA, 0.1 mM NaF, 0.02 mg/ml BSA, 10% glycerol,2 mM sodium orthovanadate, 0.25 mM DTT) for a further 10 min. Theactivated BTK was frozen in 50 μl aliquots (125-150 μg/ml).

BTK activity was assayed using a PLCγ2-derived biotinylated peptidesubstrate (biotin-EELNNQLFLYDTHQNLR-OH) and AlphaScreen™ (AmplifiedLuminescent Proximity Homogeneous Assay) technology. The extent ofpeptide phosphorylation was determined by using acceptor beadsconjugated to phosphotyrosine antibody that recognized thephosphorylated peptide and donor beads conjugated to streptavidin thatbinds to the biotin on the peptide. Excitation of the donor beadsconverted ambient oxygen to excited singlet oxygen which when in closeproximity to acceptor beads, reacted with acceptor beads resulting insignal amplification.

Test inhibitors and controls were prepared in 10% DMSO at 10-fold thedesired final concentration and added to each well of a reaction plate(Corning 96-well half-area solid white nonbinding surface plate) in avolume of 2.5 μl. Full-length activated BTK (wildtype or mutant C481S)diluted to 0.179 nM in assay buffer (50 mM Tris, pH 8, 10 mM MgCl2, 1 mMEDTA, 0.1 mM NaF, 0.02 mg/ml BSA, 10% glycerol, 0.2 mM Na3VO4, 0.1 mMbeta-glycerophosphate, 0.25 mM DTT) was added to each well in a volumeof 17.5 μl and incubated with the inhibitors for 30 min. The kinasereaction was initiated by the addition of 5 μl of biotin-PLCγ2 peptideand ATP mixture diluted in assay buffer for a final concentration in the25 μl reaction of 150 nM and 180 μM respectively and 0.125 nM enzyme.The plate was incubated for 120 min at room temperature and the reactionstopped by the addition of 10 μl stop/detection mixture containing 35 mMEDTA, 50 ug/ml AlphaScreen™ Streptavidin Donor beads (finalconcentration is 500 ng/well) and AlphaScreen™ Phospho-tyrosine(P-Tyr-100) Acceptor beads (final concentration is 500 ng/well) undergreen light conditions. The plate was incubated overnight at roomtemperature in the dark and the plates read on the BMG PolarStar Omega(excitation wavelength: 640 nm, emission wavelength: 570 nm, Gain=4000).Data were archived and analyzed with a 4-parameter fit to generate IC₅₀values using the CDD Vault from Collaborative Drug Discovery.

TABLE 4 Biological activity of Compounds of Formula (I) in BTK KinaseAssay Type A (MSA using active BTK), Assay Type B (MSA using activeBTK), and Assay Type C (radiometric assay with active enzyme). Cmpd BTKIC₅₀ Assay No. (nM) type I-1 11 A I-2 17 A I-3 19 A I-4 107 A I-5 90 AI-6 7.4 A I-7 93 A I-8 74 A I-9 6.1 A I-10 30 A I-11 151 A I-12 37 AI-13 25 A I-14 14 A I-15 8.3 A I-16 134 A I-17 80 A I-18 9.7 A I-19 9.2A I-20 9.5 A I-21 9.7 A I-22 5.9 A I-23 5.9 A I-24 6.2 A I-25 154 A I-2633 A I-27 46 A I-28 8.3 A I-29 9.3 A I-30 4.9 A I-31 9.0 A I-32 11 AI-33 4.2 A I-34 4.4 A I-35 150 A I-36 29 A I-37 15 A I-38 5.2 A I-39 3.0A I-40 10 A I-41 2.6 A I-42 5.4 A I-43 2.1 A I-44 5.4 A I-45 2.6 A I-4666 A I-47 10 A I-48 6.0 A I-49 8.6 A I-50 2.7 A I-51 1.9 A I-52 70 AI-53 76 A I-54 83 A I-55 81 A I-56 158 A I-57 63 A I-58 3.6 A I-59 6.7 AI-60 7.0 A I-61 3.4 A I-62 5.0 A I-63 3.3 A I-64 4.1 A I-65 11 A I-66 11A I-67 5.4 A I-68 5.6 A I-69 2.2 A I-70 4.6 A I-71 19 A I-72 447 A I-7366 A I-74 20 A I-75 12 A I-76 52 A I-77 56 A I-78 3.0 A I-79 3.7 A I-804.1 A I-81 5.5 A I-82 12 A I-83 19 A I-84 14 A I-85 2.3 A I-86 2.9 AI-87 4.9 A I-88 2.5 A I-89 23 A I-90 5.7 A I-91 3.5 A I-92 3.1 A I-933.4 A I-94 2.9 A I-95 8.1 A I-96 8.9 A I-97 7.0 A I-98 5.3 A I-99 4.8 AI-100 5.3 A I-101 5.1 A I-102 1.9 A I-103 3.5 A I-104 3.5 A I-105 7.0 AI-106 4.6 B I-107 12 B I-108 7.0 B I-109 3.2 B I-110 16 B I-111 3.0 BI-112 18 B I-113 3.6 B I-114 23 B I-115 5.8 B I-116 5.9 B I-117 5.9 BI-118 4.4 B I-119 5.1 B I-120 121 B I-121 7.3 B I-122 0.77 A I-123 0.85C I-124 9.7 C I-125 0.56 C I-126 2.4 C I-127 1.63 B I-128 15 A I-129 34A I-130 3.2 B I-131 3.8 B I-132 12 A I-133 188 A I-134 292 A I-135 63 AI-136 154 A I-137 95 A I-138 41 A I-139 2.3 A I-140 8.0 A I-141 2.2 AI-142 6.8 A I-143 2359 A I-144 9.2 A I-145 7.2 A I-146 3.9 A I-147 7.5 AI-148 12 A I-149 89 A I-150 0.93 A I-151 1.3 A I-152 133 A I-153 27 AI-154 32 A I-155 9.3 A I-156 30 A I-157 4.0 A I-158 9.6 A I-159 15 AI-160 6.0 A I-161 102 A I-162 45 A I-163 29 A I-164 19 A I-165 8.4 AI-166 1.1 A I-167 1.4 A I-168 7.2 A I-169 1.7 A I-170 7.0 A I-171 39 AI-172 20 A I-173 4.3 A I-174 7.2 A I-175 3.1 B I-176 2.5 B I-177 1.7 BI-178 2.2 B I-179 1.8 B I-180 1.8 B I-181 0.98 B I-182 1.5 B I-183 2.2 BI-184 61 B I-185 57 B I-186 12 B I-187 4.2 B I-188 1.7 B I-189 17 BI-190 17 B I-191 37 B I-192 4.4 B I-193 1.2 B I-194 1.5 B I-195 2.2 BI-196 3.2 B I-197 1.6 B I-198 2.6 B I-199 6.8 B I-200 1.4 B I-201 1.5 BI-202 1.0 B I-203 1.4 B I-204 1.1 B I-205 1.6 B I-206 1.8 B I-207 4.1 BI-208 3.1 B I-209 4.0 B I-210 1.9 B I-211 2.9 B I-212 2.9 B I-213 2.5 BI-214 7.4 B I-215 3.9 B I-216 1.9 B I-217 3.2 B I-218 470 A I-219 >4000A I-220 14 A I-221 >4000 A I-222 5.4 A I-223 >4000 A I-224 >4000 AI-225 >4000 A I-226 364 A I-227 >4000 A I-228 4300 A I-229 2195 A I-2304000 A

TABLE 5a Biological activity of Compounds of Formula (I) in BTKwild-type and BTK mutant C481S Kinase Assay (radiometric assay).Compound BTK BTK-C481S No. IC₅₀ (nM) IC₅₀ (nM) I-123 0.85 0.39 I-124 9.77.0 I-125 0.56 0.37 I-126 2.4 0.79

TABLE 5b Biological activity of Compounds of Formula (I) in BTKwild-type and BTK mutant C481S Kinase Assay (AlphaScreen). Compound BTKBTK-C481S IC₅₀ No. IC₅₀ (nM) (nM) I-601 20.9 116 I-602 140 317 I-603 4661770 I-604 304 731 I-605 467 1860 I-606 0.98 55.9 I-607 13.8 216 I-6088.19 187 I-609 114 519 I-236 181 98.4 I-610 491 1150 I-611 1140 1510I-612 1630 82% @ 10 uM I-613 87% @ 10 uM 64% @ 10 uM I-614 142 228 I-256156 317 I-615 86.4 34.1 I-616 116 506 I-617 16.2 48.7 I-618 87.4 399I-619 376 942 I-246 103 514 I-620 598 70% @ 10 uM I-621 571 85% @ 10 uMI-622 847 62% @ 10 uM I-623 124 185 I-624 1210 53% @ 10 uM I-625 110 170I-626 164 757 I-627 777 664 I-628 59.7 161 I-629 89.5 804 I-630 18.4 189I-631 52.1 177 I-632 84% @ 10 uM 66% @ 10 uM I-633 77% @ 10 uM 50% @ 10uM I-634 619.5 690 I-635 73% @ 10 uM 49% @ 10 uM I-636 62% @ 10 uM 41% @10 uM I-637 76% @ 10 uM 55% @ 10 uM I-638 63% @ 10 uM 54% @ 10 uM I-231318 248 I-276 17.6 58 I-639 14.2 25.6 I-640 69.5 203 I-641 8.28 32.6I-642 251 203 I-643 269 150 I-644 58% @ 10 uM 44% @ 10 uM I-645 743 81%@ 10 uM I-311i 867 81% @ 10 uM I-646 380 781 I-647 1440 108 I-318i 423714 I-317i 40.7 156 I-648 731 810 I-649 959 82% @ 10 uM I-650 202 326I-320 336 63.1 I-319 444 127 I-651 332 230 I-652 177 497 I-324r 17.2 105I-328r 0.98 18.4 I-321r 4.5 179 I-325r 0.98 136 I-322r 10.4 98.6 I-326r4.33 419 I-653 10 38.8 I-343r 11 34 I-654 6.55 20.7 I-345e 10.1 68.2I-342e 14.2 33.4 I-655 44.5 52 I-656 123 254 I-369e 19.8 137 I-370e 59.549.8 I-657 236 832 I-362e 35.6 44.5 I-359e 29.4 124 I-360e 1.07 59.4

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, wherein: A is (C₆-C₁₀) aryl or 5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S,wherein the aryl and heteroaryl are optionally substituted with one ormore R₄; R₁ is (C₃-C₇) cycloalkyl or 4- to 9-membered heterocyclylcomprising 1 to 3 heteroatoms selected from N, O, and S, wherein thecycloalkyl and heterocyclyl are optionally substituted with one or moreR₅; R₂ is H or (C₁-C₄) alkyl; or when q is 0, R₁ and R₂ together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclyl ring comprising 0 to 1 additional heteroatoms selected fromN, O, and S and optionally substituted with one or more NR₆R₇; R₃ is Hor N(R₅)₂; each R₄ is independently (i) (C₁-C₄) alkyl, (ii) (C₁-C₄)alkoxy optionally substituted with one or more (C₁-C₄) alkoxy, (iii)(C₁-C₄) haloalkyl, (iv) (C₁-C₄) haloalkoxy, (v) halogen, (vi)NR₉S(O)_(p)R₁₀, (vii) O(CH₂)_(n)R₁₁, (viii) NH(CH₂)_(n)R₁₁1, (ix)(CH₂)_(n)C(═O)NHR₂₅, (x) (CH₂)_(n)NHC(═O)R₂₅, (xi)(CH₂)_(n)NHC(═O)NHR₂₅, (xii) C(═O)R₂₅, or (xiii) heterocyclyl comprisingone or two 4- to 6-membered rings and 1 to 3 heteroatoms selected fromN, O, and S and optionally substituted with one or more substituentsselected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, C(═O)(C₁-C₄) alkyl, andhalogen; each R₅ is independently (i) (C₁-C₆) alkyl optionallysubstituted with one or more (C₁-C₄) alkoxy or phenyl, (ii) (C₂-C₄)alkenyl optionally substituted with one or more C(═O)(C₁-C₄) alkyl,(iii) (C(R₁₂)₂)_(r)OH, (iv) (C(R₁₂)₂)_(r)NR₁₃R₁₄, (v) C(═O)OH, (vi)C(═O)O(C₁-C₄) alkyl, (vii) C(═O)NR₁₃R₁₅, (viii) C(═O)R₁₆, (ix)S(O)_(p)R₁₆, or (x) 5- or 6-membered heteroaryl comprising 1 to 3heteroatoms selected from N, O, and S and optionally substituted withone or more (C₁-C₄) alkyl, (xi) or two R₅ together with the carbon atomto which they are attached form (═O), or (xii) two R₅ together with theatoms to which they are attached form a bridged 3- to 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS; R₆ is H or (C₁-C₄) alkyl; R₇ is H, (C₁-C₄) alkyl, or C(═O)R₂₄; eachR₈ is independently (i) H, (ii) (C₁-C₄) alkyl, or (iii) 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S andoptionally substituted with one or more (C₁-C₄) alkyl, or (iv) two R₈together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclyl ring comprising 0 to 1 additional heteroatomsselected from N, O, and S and optionally substituted with one or more(C₁-C₄) alkyl; R₉ is H or (C₁-C₄) alkyl; R₁₀ is (C₁-C₄) alkyl or(C₆-C₁₀) aryl; R₁₁ is (C₃-C₇) cycloalkyl, (C₄-C₇) cycloalkenyl, (C₆-C₁₀)aryl, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S, wherein the aryl and heteroaryl areoptionally substituted with one or more R₁₇; each R₁₂ is independently Hor (C₁-C₆) alkyl; R₁₃ is H or (C₁-C₄) alkyl; R₁₄ is (i) H, (ii) (C₁-C₄)alkyl, (iii) (C(R₁₈)₂)_(r)C(═O)NR₁₉R₂₀, (iv) (CH₂)_(n)(C₆-C₁₀) aryloptionally substituted with one or more (C₁-C₄) alkyl or halogen, (v)C(═O)R₂₁, (vi) C(═O)O(C₁-C₄) alkyl, (vii) S(O)₂(C₁-C₈) alkyl, (viii)S(O)₂NH(C₁-C₈) alkyl, (ix) S(O)₂N((C₁-C₈) alkyl)₂, or (x) C(═O)(C₁-C₈)alkyl optionally substituted with one or more R₂₂; or R₁₃ and R₁₄together with the nitrogen atom to which they are attached form a 4- to6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected fromN, O, and S and optionally substituted with one or more substituentsselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, OH, NH₂, and (═O); R₁₅ is(i) H, (ii) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatomsselected from N, O, and S, or (iii) (C₁-C₄) alkyl optionally substitutedwith one or more substituents selected from OH, 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S,and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom N, O, and S; or R₁₃ and R₁₅ together with the nitrogen atom towhich they are attached form a 4- to 6-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S and optionallysubstituted with one or more substituents selected from (C₁-C₄) alkyl,(C₁-C₄) alkoxy, and OH, or form a 5- to 8-membered bicyclic heterocyclylring comprising 1 to 3 heteroatoms selected from N, O, and S andoptionally substituted with one or more substituents selected from(C₁-C₄) alkyl, (C₁-C₄) alkoxy, and OH; R₁₆ is (C₁-C₄) alkyl, (C₂-C₄)alkenyl, (C₂-C₄) alkynyl, or 3- to 6-membered heterocyclyl comprising 1to 3 heteroatoms selected from N, O, and S, wherein the alkyl, alkenyl,and alkynyl are optionally substituted with one or more substituentsselected from (C₁-C₄) alkoxy, O-phenyl, halogen, CN, NH₂, (C₁-C₄)alkylamino, di-(C₁-C₄) alkylamino, and OS(O)₂(C₁-C₄) alkyl, and whereinthe heterocyclyl is optionally substituted with one or more R₂₃; eachR₁₇ is independently (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl,(C₁-C₄) haloalkoxy, halogen, C(═O)NH₂, C(═O)NH(C₁-C₄) alkyl, orC(═O)N((C₁-C₄) alkyl)₂; each R₁₈ is independently H or (C₁-C₄) alkyl;R₁₉ is H or (C₁-C₄) alkyl; R₂₀ is H or (CH₂)_(n)(C₆-C₁₀) aryl optionallysubstituted with one or more (C₁-C₄) alkyl; R₂₁ is (C₃-C₇) cycloalkyl,5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selectedfrom N, O, and S, (C₆-C₁₀) aryl, or 5- or 6-membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O, and S, wherein thearyl, heteroaryl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from (C₁-C₄) alkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, OH, and halogen;each R₂₂ is independently (i) (C₁-C₄) alkoxy, (ii) OH, (iii) NH₂, (iv)(C₁-C₄) alkylamino, (v) di-(C₁-C₄) alkylamino, or (vi) 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S andoptionally substituted with one or more substituents selected from (a)(C₁-C₄) alkyl, (b) (CH₂)_(x)(C₆-C₁₀) aryl, and (c) C(═O)(C₆-C₁₀)aryloptionally substituted with one or more (C₁-C₄) alkyl; each R₂₃ isindependently (C₁-C₄) alkyl or C(═O)(C₁-C₄) alkyl, or two R₂₃ togetherwith the atoms to which they are attached form a 5- or 6-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS; R₂₄ is (C₁-C₄) alkyl optionally substituted with one or moresubstituents selected from (C₁-C₄) alkoxy and 5- or 6-memberedheterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S;R₂₅ is (C₁-C₄) alkyl optionally substituted with one or more (C₁-C₄)alkoxy, (C(R₂₆)₂)_(x)(C₆-C₁₀) aryl, (C(R₂₆)₂)_(x)-heteroaryl, whereinthe heteroaryl comprises one or two 5- or 6-membered rings and 1 to 3heteroatoms selected from N, O, and S, or (C(R₂₆)₂)_(x)-heterocyclyl,wherein the heterocyclyl comprises one or two 4- to 6-membered rings and1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, alkoxy,aryl, heteroaryl, and heterocyclyl are optionally substituted with oneor more substituents selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, cyano, halogen, OH, NH₂, (C₆-C₁₀)aryl, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from N, O, and S; each R₂₆ is independently H or (C₁-C₄) alkyl,or two R₂₆ together with the atom to which they are attached form a(C₃-C₆) cycloalkyl ring or 3- or 6-membered heterocyclyl ring comprising1 to 3 heteroatoms selected from N, O, and S; each n and each p isindependently 0, 1, or 2; each r is independently 0, 1, 2, or 3; each qand each x is independently 0, 1, 2, or 3; and provided that when R₄ isNR₉S(O)_(p)R₁₀, A is optionally substituted with one additional R₄; andprovided that the compound is not(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.2. The compound of claim 1, wherein A is phenyl, thiophenyl, orpyridinyl optionally substituted with one or more R₄.
 3. The compound ofclaim 1, wherein A is phenyl, thiophenyl, or pyridinyl substituted withone to two R₄.
 4. The compound of claim 1, wherein A is phenylsubstituted with one to two R₄.
 5. The compound of claim 1, wherein R₂is H.
 6. The compound of claim 1, wherein R₃ is H, NH₂, NHCH₃, or4-methylpiperazine.
 7. The compound of claim 1, wherein R₃ is H.
 8. Thecompound of claim 1, wherein each R₄ is independently (C₁-C₄) alkyl,(C₁-C₄) alkoxy optionally substituted with one or more (C₁-C₄) alkoxy,halogen, NR₉S(O)_(p)R₁₀, O(CH₂)_(n)R₁₁, NH(CH₂)_(n)R₁₁,(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅,C(═O)R₂₅, or heterocyclyl comprising one or two 4- to 6-membered ringsand 1 to 3 heteroatoms selected from N, O, and S and optionallysubstituted with one or more substituents selected from (C₁-C₄) alkyl,(C₁-C₄) haloalkyl, C(═O)(C₁-C₄) alkyl, and halogen.
 9. The compound ofclaim 1, wherein each R₄ is independently (C₁-C₄) alkyl, (C₁-C₄) alkoxyoptionally substituted with one or more (C₁-C₄) alkoxy, halogen,(CH₂)_(n)C(═O)NHR₂₅, (CH₂)_(n)NHC(═O)R₂₅, (CH₂)_(n)NHC(═O)NHR₂₅, orC(═O)R₂₅.
 10. The compound of claim 1, wherein at least one R₄ isC(═O)NHR₂₅, NHC(═O)R₂₅, (CH₂)C(═O)NHR₂₅, or (CH₂)NHC(═O)R₂₅.
 11. Thecompound of claim 1, wherein at least one R₄ is (CH₂)NHC(═O)R₂₅.
 12. Thecompound of claim 1, wherein at least one R₄ is heterocyclyl comprisingone or two 4- to 6-membered rings and 1 to 3 heteroatoms selected fromN, O, and S and optionally substituted with one or more substituentsselected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, C(═O)(C₁-C₄) alkyl, andhalogen.
 13. The compound of claim 1, wherein R₁₁ is (C₆-C₁₀) aryl or 5-or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N,O, and S, wherein the aryl and heteroaryl are optionally substitutedwith one to three R₁₇.
 14. The compound of claim 1, wherein R₁₁ isphenyl or pyridinyl, and is optionally substituted with one to threeR₁₇.
 15. The compound of claim 1, wherein R₁ is (C₄-C₇) cycloalkylsubstituted with one to three R₅.
 16. The compound of claim 1, whereinR₁ is cyclohexyl substituted with one to three R₅.
 17. The compound ofclaim 1, wherein R₁ is 4- to 7-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S optionally substituted with one tothree R₅.
 18. The compound of claim 1, wherein R₁ is piperidinyl,tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyloptionally substituted with one to three R₅.
 19. The compound of claim1, wherein R₁ is tetrahydropyranyl optionally substituted with one tothree R₅.
 20. The compound of claim 1, wherein R₅ is C(═O)R₁₆ orS(O)_(p)R₁₆ and R₁₆ is (C₂-C₄) alkenyl or (C₂-C₄) alkynyl, wherein thealkenyl and alkynyl are optionally substituted with one or more CN. 21.The compound of claim 1, wherein two R₅ together with the atoms to whichthey are attached form a bridged 3- to 6-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S.
 22. Thecompound of claim 1, wherein q is 0 or
 1. 23. The compound of claim 1,wherein the compound is of Formula (Ia′), (Ib′), or (Ic′):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, wherein w is 1 or
 2. 24. The compound of claim 1,wherein the compound is of Formula (Id′), (Ie′), or (If′):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof, wherein R₅′ is H or R₅.
 25. The compound of claim1, wherein the compound is of any of Formulae (Ig1)-(Ig12),(Ih1)-(Ih12), and (Ii1)-(Ii12):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,or tautomer thereof.
 26. A pharmaceutical composition comprising acompound of claim 1, or a pharmaceutically acceptable salt, solvate,prodrug, stereoisomer, or tautomer thereof, and a pharmaceuticallyacceptable diluent, excipient or carrier.
 27. A method of treating aBTK-mediated disorder, comprising administering to a subject in needthereof a compound of claim 1, or a pharmaceutically acceptable salt,solvate, prodrug, stereoisomer, or tautomer thereof.